Tumor microenvironment governs the prognostic landscape of immunotherapy for head and neck squamous cell carcinoma: A computational model-guided analysis

Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent pro...

Full description

Saved in:
Bibliographic Details
Published inPLoS computational biology Vol. 21; no. 6; p. e1013127
Main Authors Bhattacharya, Priyan, Linnenbach, Alban, South, Andrew P., Martinez-Outschoorn, Ubaldo, Curry, Joseph M., Johnson, Jennifer M., Harshyne, Larry A., Mahoney, Mỹ G., Luginbuhl, Adam J., Vadigepalli, Rajanikanth
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 03.06.2025
Public Library of Science (PLoS)
Subjects
Biology and Life Sciences
Care and treatment
Computational Biology
Computer Simulation
Ecology and Environmental Sciences
Head and Neck Neoplasms - immunology
Head and Neck Neoplasms - pathology
Head and Neck Neoplasms - therapy
Humans
Immune Checkpoint Inhibitors - therapeutic use
Immunotherapy
Immunotherapy - methods
Medicine and Health Sciences
Methods
Models, Biological
Prognosis
Squamous cell carcinoma
Squamous Cell Carcinoma of Head and Neck - immunology
Squamous Cell Carcinoma of Head and Neck - pathology
Squamous Cell Carcinoma of Head and Neck - therapy
Tumor Microenvironment - immunology
United States
Online AccessGet full text
ISSN1553-7358
1553-734X
1553-7358
DOI10.1371/journal.pcbi.1013127

Cover

Abstract Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly mediated paracrine interactions. Simulation across the selected parameter space of the HNSCC TME network shows that distinct mechanistic balances within the TME give rise to the five clinically observed TME subtypes such as immune/non-fibrotic, immune/fibrotic, fibrotic only and immune/fibrotic desert. We predict that the cancer-associated fibroblast, beyond a critical proliferation rate, drastically worsens the ICI response by hampering the accessibility of the CD8 + killer T cells to the tumor cells. Our analysis reveals that while an Interleukin-2 (IL-2) + ICI combination therapy may improve response in the immune desert scenario, Osteopontin (OPN) and Leukemia Inhibition Factor (LIF) knockout with ICI yields the best response in a fibro-dominated scenario. Further, we predict Interleukin-8 (IL-8), and lactate can serve as crucial biomarkers for ICI-resistant HNSCC phenotypes. Overall, we provide an integrated quantitative framework that explains a wide range of TME-mediated resistance mechanisms for HNSCC and predicts TME subtype-specific targets that can lead to an improved ICI outcome.
AbstractList Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly mediated paracrine interactions. Simulation across the selected parameter space of the HNSCC TME network shows that distinct mechanistic balances within the TME give rise to the five clinically observed TME subtypes such as immune/non-fibrotic, immune/fibrotic, fibrotic only and immune/fibrotic desert. We predict that the cancer-associated fibroblast, beyond a critical proliferation rate, drastically worsens the ICI response by hampering the accessibility of the CD8 + killer T cells to the tumor cells. Our analysis reveals that while an Interleukin-2 (IL-2) + ICI combination therapy may improve response in the immune desert scenario, Osteopontin (OPN) and Leukemia Inhibition Factor (LIF) knockout with ICI yields the best response in a fibro-dominated scenario. Further, we predict Interleukin-8 (IL-8), and lactate can serve as crucial biomarkers for ICI-resistant HNSCC phenotypes. Overall, we provide an integrated quantitative framework that explains a wide range of TME-mediated resistance mechanisms for HNSCC and predicts TME subtype-specific targets that can lead to an improved ICI outcome.
Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly mediated paracrine interactions. Simulation across the selected parameter space of the HNSCC TME network shows that distinct mechanistic balances within the TME give rise to the five clinically observed TME subtypes such as immune/non-fibrotic, immune/fibrotic, fibrotic only and immune/fibrotic desert. We predict that the cancer-associated fibroblast, beyond a critical proliferation rate, drastically worsens the ICI response by hampering the accessibility of the CD8 + killer T cells to the tumor cells. Our analysis reveals that while an Interleukin-2 (IL-2) + ICI combination therapy may improve response in the immune desert scenario, Osteopontin (OPN) and Leukemia Inhibition Factor (LIF) knockout with ICI yields the best response in a fibro-dominated scenario. Further, we predict Interleukin-8 (IL-8), and lactate can serve as crucial biomarkers for ICI-resistant HNSCC phenotypes. Overall, we provide an integrated quantitative framework that explains a wide range of TME-mediated resistance mechanisms for HNSCC and predicts TME subtype-specific targets that can lead to an improved ICI outcome.Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly mediated paracrine interactions. Simulation across the selected parameter space of the HNSCC TME network shows that distinct mechanistic balances within the TME give rise to the five clinically observed TME subtypes such as immune/non-fibrotic, immune/fibrotic, fibrotic only and immune/fibrotic desert. We predict that the cancer-associated fibroblast, beyond a critical proliferation rate, drastically worsens the ICI response by hampering the accessibility of the CD8 + killer T cells to the tumor cells. Our analysis reveals that while an Interleukin-2 (IL-2) + ICI combination therapy may improve response in the immune desert scenario, Osteopontin (OPN) and Leukemia Inhibition Factor (LIF) knockout with ICI yields the best response in a fibro-dominated scenario. Further, we predict Interleukin-8 (IL-8), and lactate can serve as crucial biomarkers for ICI-resistant HNSCC phenotypes. Overall, we provide an integrated quantitative framework that explains a wide range of TME-mediated resistance mechanisms for HNSCC and predicts TME subtype-specific targets that can lead to an improved ICI outcome.
Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly mediated paracrine interactions. Simulation across the selected parameter space of the HNSCC TME network shows that distinct mechanistic balances within the TME give rise to the five clinically observed TME subtypes such as immune/non-fibrotic, immune/fibrotic, fibrotic only and immune/fibrotic desert. We predict that the cancer-associated fibroblast, beyond a critical proliferation rate, drastically worsens the ICI response by hampering the accessibility of the CD8 + killer T cells to the tumor cells. Our analysis reveals that while an Interleukin-2 (IL-2) + ICI combination therapy may improve response in the immune desert scenario, Osteopontin (OPN) and Leukemia Inhibition Factor (LIF) knockout with ICI yields the best response in a fibro-dominated scenario. Further, we predict Interleukin-8 (IL-8), and lactate can serve as crucial biomarkers for ICI-resistant HNSCC phenotypes. Overall, we provide an integrated quantitative framework that explains a wide range of TME-mediated resistance mechanisms for HNSCC and predicts TME subtype-specific targets that can lead to an improved ICI outcome. Increasing evidence suggests that the onset, progression, and lack of/no response of Head and Neck Squamous cell carcinoma (HNSCC) to immune checkpoint inhibitor (ICI) are emergent properties arising from the interactions within the tumor microenvironment (TME). Developing a mechanistic insights into how the compositional diversity of the TME determines the outcome of immunotherapy remains largely unexplored in the context of HNSCC. In this work, we developed a mathematical model that integrates the existing knowledge about the diverse forms of cytokines mediated cell-cell interactions (paracrine, autocrine, transition) within the TME to unpack (a) the mechanisms behind the emergence of different clinically observed TME subtypes such as fibrotic only, immune/fibrotic, non-fibrotic, and desert and (b) how these subtypes govern the response to immunotherapy. Subsequently, the model-guided approach enables us to propose potential biomarkers (IL-8, and lactate) for resistant phenotypes, and to identify subtype-specific target species (IL2 for fibrotic only, OPN and LIF knockout for a subclass of immune/fibrotic) for circumventing ICI resistance. Overall, the integrated quantitative framework explains a wide range of TME-mediated resistance mechanisms for HNSCC and predicts TME subtype-specific targets that can lead to an improved ICI outcome.
Audience Academic
Author South, Andrew P.
Luginbuhl, Adam J.
Linnenbach, Alban
Harshyne, Larry A.
Curry, Joseph M.
Vadigepalli, Rajanikanth
Bhattacharya, Priyan
Johnson, Jennifer M.
Martinez-Outschoorn, Ubaldo
Mahoney, Mỹ G.
AuthorAffiliation 4 Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
2 Department of Otolaryngology, Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
1 Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
National Institutes of Health (NIH), UNITED STATES OF AMERICA
5 Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
3 Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
AuthorAffiliation_xml – name: 5 Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
– name: 1 Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
– name: 2 Department of Otolaryngology, Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
– name: National Institutes of Health (NIH), UNITED STATES OF AMERICA
– name: 4 Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
– name: 3 Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
Author_xml – sequence: 1
  givenname: Priyan
  orcidid: 0000-0001-6757-1789
  surname: Bhattacharya
  fullname: Bhattacharya, Priyan
– sequence: 2
  givenname: Alban
  surname: Linnenbach
  fullname: Linnenbach, Alban
– sequence: 3
  givenname: Andrew P.
  surname: South
  fullname: South, Andrew P.
– sequence: 4
  givenname: Ubaldo
  surname: Martinez-Outschoorn
  fullname: Martinez-Outschoorn, Ubaldo
– sequence: 5
  givenname: Joseph M.
  surname: Curry
  fullname: Curry, Joseph M.
– sequence: 6
  givenname: Jennifer M.
  surname: Johnson
  fullname: Johnson, Jennifer M.
– sequence: 7
  givenname: Larry A.
  surname: Harshyne
  fullname: Harshyne, Larry A.
– sequence: 8
  givenname: Mỹ G.
  surname: Mahoney
  fullname: Mahoney, Mỹ G.
– sequence: 9
  givenname: Adam J.
  surname: Luginbuhl
  fullname: Luginbuhl, Adam J.
– sequence: 10
  givenname: Rajanikanth
  orcidid: 0000-0002-8405-1037
  surname: Vadigepalli
  fullname: Vadigepalli, Rajanikanth
BackLink https://www.ncbi.nlm.nih.gov/pubmed/40460357$$D View this record in MEDLINE/PubMed
BookMark eNptkl2P1CAUhhuzxv3Qf2AMiTd6MWNpoQzemMnGj0k2MdH1mpzCaYexhS60G-en-G-lzrjZSQwXwOE5L5zDe5mdOe8wy17SfElLQd_t_BQcdMtB13ZJc1rSQjzJLijn5UKUfHX2aH2eXca4y_O0lNWz7JzlrEobcZH9vp16H0hvdfDo7m3wrkc3ktbfY3CRjFskQ_Ct83G0mnTgTNQwIPENsX0_OZ-IAMOeNElmi2BIQohD_ZPEuwl6P0WiseuIhqCt8z28J2uifT9MI4zWpxJI7w12i3ayBud06PbRxufZ0wa6iC-O81X249PH2-svi5uvnzfX65uF5oUYF7yqRSmFLASscmmEqRtAWQvDeINQr0DkCAC0Lisq80IzzSQyrSsukMlallfZ5qBrPOzUEGwPYa88WPU34EOrIKTaO1SiWDWsNk3DtGFYaclKnktueFlQMKxKWh8OWsNU92h06mSA7kT09MTZrUqtVrSgVUHzMim8OSoEfzdhHFVv49w_cJhaqdJNnItCyvnhrw9oC-lt1jU-SeoZV-sVq6q84ownavkfKg2D6dOTpRqb4icJb08SEjPir7GFKUa1-f7tlH31uN6HQv_5KwHsACR7xRiweUBormYbq6ON1WxjdbRx-QdL-uvb
Cites_doi 10.1038/s41571-019-0175-7
10.1038/s41467-023-40850-5
10.1073/pnas.192461099
10.1158/1078-0432.CCR-05-0641
10.1016/j.omto.2023.100740
10.3390/pr7010037
10.1038/s41467-023-41518-w
10.7554/eLife.00747
10.4161/cam.20377
10.1038/s41467-021-25548-w
10.1016/B978-1-4557-4066-6.00033-0
10.1038/s41416-023-02361-4
10.1038/s41467-019-13091-8
10.1158/1078-0432.CCR-21-1816
10.3390/ijms24043497
10.1016/j.cell.2017.10.044
10.3390/ijms22136995
10.1111/j.1365-3083.2009.02308.x
10.1016/j.jtbi.2019.110136
10.1038/sj.embor.7401099
10.1002/JLB.2MR0220-549R
10.1016/j.jtbi.2019.03.002
10.1038/s41467-019-10369-9
10.1111/j.1365-2184.2011.00739.x
10.3390/cancers12113244
10.1016/j.celrep.2024.114392
10.3389/fimmu.2022.964442
10.1007/s00018-016-2226-x
10.3390/cancers13184720
10.1038/cddis.2015.162
10.1101/gr.275308.121
10.1016/j.coisb.2021.100377
10.1038/onc.2014.410
10.1186/s13046-022-02481-4
10.3389/fimmu.2023.1104771
10.1109/TAC.2021.3056582
10.1158/1078-0432.CCR-14-2481
10.1186/s12943-023-01826-7
10.1038/s41577-019-0221-9
10.1186/s40364-020-00228-x
10.1016/j.ccell.2021.04.014
10.1016/j.ccell.2023.02.016
10.1016/j.jtbi.2015.10.034
10.1126/scitranslmed.abo5409
10.1111/1759-7714.14998
10.1016/j.cell.2011.07.026
10.1016/j.isci.2022.105499
10.1038/s41540-022-00244-7
10.1034/j.1398-9995.1999.00099.x
10.3390/jcm9020295
10.1146/annurev.immunol.15.1.563
10.1038/bjc.1990.184
10.1038/s41467-021-21554-0
10.3390/ijms222011027
10.1002/mc.23587
10.1172/jci.insight.87030
10.1016/j.phrs.2019.04.030
10.1002/hed.25930
10.1038/s41388-019-0688-7
10.1038/s41416-020-01048-4
10.3389/fonc.2019.00827
10.1158/1078-0432.CCR-15-0685
10.1038/s41568-018-0083-7
10.1007/s12026-008-8032-2
10.1002/hed.26036
10.3389/fimmu.2023.1208870
10.1080/2162402X.2017.1315488
10.1097/CJI.0000000000000149
10.1038/nmeth.1315
10.3389/fnut.2023.1113739
10.1093/carcin/bgaa116
10.1038/s41591-018-0136-1
10.1016/S1471-4906(02)02302-5
10.1172/JCI123360
10.1016/j.physd.2008.03.044
10.1038/s41568-019-0238-1
10.1007/s00018-009-0026-2
10.1158/1078-0432.CCR-16-0224
10.1371/journal.pcbi.1004881
10.3389/fonc.2024.1412212
10.3390/ijtm2030033
10.3389/fendo.2023.1212749
10.1038/s41388-021-01663-2
10.1186/s12964-020-00627-5
10.3892/ijo.2014.2393
10.1016/j.xcrm.2024.101399
10.3390/curroncol29050247
10.1038/s41572-020-00224-3
10.1007/s00262-006-0272-1
10.1016/j.pharmthera.2020.107692
10.1016/j.oraloncology.2021.105420
10.1038/ncomms10204
10.1038/s41420-021-00556-3
10.3390/cells11172630
10.1016/j.ccell.2022.07.006
10.1016/0025-5564(90)90021-P
10.1172/JCI17129
10.1016/j.semcancer.2015.02.006
10.1186/s12943-021-01428-1
10.1200/JCO.2006.06.8627
10.3390/cancers14030744
10.1016/j.ymthe.2022.12.016
10.1016/j.bbcan.2018.10.006
ContentType Journal Article
Copyright Copyright: © 2025 Bhattacharya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
COPYRIGHT 2025 Public Library of Science
2025 Bhattacharya et al 2025 Bhattacharya et al
Copyright_xml – notice: Copyright: © 2025 Bhattacharya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
– notice: COPYRIGHT 2025 Public Library of Science
– notice: 2025 Bhattacharya et al 2025 Bhattacharya et al
DBID AAYXX
CITATION
CGR
CUY
CVF
ECM
EIF
NPM
ISR
7X8
5PM
DOA
DOI 10.1371/journal.pcbi.1013127
DatabaseName CrossRef
Medline
MEDLINE
MEDLINE (Ovid)
MEDLINE
MEDLINE
PubMed
Gale In Context: Science
MEDLINE - Academic
PubMed Central (Full Participant titles)
DOAJ Directory of Open Access Journals
DatabaseTitle CrossRef
MEDLINE
Medline Complete
MEDLINE with Full Text
PubMed
MEDLINE (Ovid)
MEDLINE - Academic
DatabaseTitleList MEDLINE
CrossRef


MEDLINE - Academic
Database_xml – sequence: 1
  dbid: DOA
  name: DOAJ Directory of Open Access Journals
  url: https://www.doaj.org/
  sourceTypes: Open Website
– sequence: 2
  dbid: NPM
  name: PubMed
  url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
  sourceTypes: Index Database
– sequence: 3
  dbid: EIF
  name: MEDLINE
  url: https://proxy.k.utb.cz/login?url=https://www.webofscience.com/wos/medline/basic-search
  sourceTypes: Index Database
DeliveryMethod fulltext_linktorsrc
Discipline Biology
DocumentTitleAlternate Computational modeling of the tumor microenvironment in head and neck cancers
EISSN 1553-7358
ExternalDocumentID oai_doaj_org_article_728f4bdff4cd4e6c9435095d5321ad46
PMC12162103
A846606545
40460357
10_1371_journal_pcbi_1013127
Genre Journal Article
GeographicLocations United States
GeographicLocations_xml – name: United States
GrantInformation_xml – fundername: NCI NIH HHS
  grantid: P30 CA056036
– fundername: NCI NIH HHS
  grantid: R01 CA244522
– fundername: ;
– fundername: ;
  grantid: P30 CA056036
– fundername: ;
  grantid: R01 CA244522
GroupedDBID ---
123
29O
2WC
53G
5VS
7X7
88E
8FE
8FG
8FH
8FI
8FJ
AAFWJ
AAKPC
AAUCC
AAWOE
AAYXX
ABDBF
ABUWG
ACGFO
ACIHN
ACIWK
ACPRK
ACUHS
ADBBV
AEAQA
AENEX
AEUYN
AFKRA
AFPKN
AFRAH
AHMBA
ALIPV
ALMA_UNASSIGNED_HOLDINGS
AOIJS
ARAPS
AZQEC
B0M
BAWUL
BBNVY
BCNDV
BENPR
BGLVJ
BHPHI
BPHCQ
BVXVI
BWKFM
CCPQU
CITATION
CS3
DIK
DWQXO
E3Z
EAP
EAS
EBD
EBS
EJD
EMK
EMOBN
ESX
F5P
FPL
FYUFA
GNUQQ
GROUPED_DOAJ
GX1
HCIFZ
HMCUK
HYE
IAO
IGS
INH
INR
ISN
ISR
ITC
J9A
K6V
K7-
KQ8
LK8
M1P
M7P
O5R
O5S
OK1
OVT
P2P
P62
PHGZM
PHGZT
PIMPY
PQQKQ
PROAC
PSQYO
PV9
RNS
RPM
RZL
SV3
TR2
TUS
UKHRP
WOW
XSB
~8M
ADRAZ
C1A
CGR
CUY
CVF
ECM
EIF
H13
IPNFZ
M48
NPM
PJZUB
PPXIY
PQGLB
RIG
WOQ
7X8
PUEGO
5PM
ID FETCH-LOGICAL-c527t-56b7397927a809d7dbfae9b7d45feab8a70eaaa1b361902c4c49e4cc657e49b93
IEDL.DBID M48
ISSN 1553-7358
1553-734X
IngestDate Wed Aug 27 01:30:10 EDT 2025
Thu Aug 21 18:24:34 EDT 2025
Fri Sep 05 15:56:18 EDT 2025
Wed Jul 16 16:53:07 EDT 2025
Tue Jul 15 03:51:55 EDT 2025
Sat Jul 12 02:48:24 EDT 2025
Mon Jul 21 05:36:09 EDT 2025
Thu Jul 03 08:38:20 EDT 2025
IsDoiOpenAccess true
IsOpenAccess true
IsPeerReviewed true
IsScholarly true
Issue 6
Language English
License Copyright: © 2025 Bhattacharya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
LinkModel DirectLink
MergedId FETCHMERGED-LOGICAL-c527t-56b7397927a809d7dbfae9b7d45feab8a70eaaa1b361902c4c49e4cc657e49b93
Notes new_version
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
The authors have declared that no competing interests exist.
ORCID 0000-0001-6757-1789
0000-0002-8405-1037
OpenAccessLink http://journals.scholarsportal.info/openUrl.xqy?doi=10.1371/journal.pcbi.1013127
PMID 40460357
PQID 3215572999
PQPubID 23479
PageCount e1013127
ParticipantIDs doaj_primary_oai_doaj_org_article_728f4bdff4cd4e6c9435095d5321ad46
pubmedcentral_primary_oai_pubmedcentral_nih_gov_12162103
proquest_miscellaneous_3215572999
gale_infotracmisc_A846606545
gale_infotracacademiconefile_A846606545
gale_incontextgauss_ISR_A846606545
pubmed_primary_40460357
crossref_primary_10_1371_journal_pcbi_1013127
PublicationCentury 2000
PublicationDate 20250603
PublicationDateYYYYMMDD 2025-06-03
PublicationDate_xml – month: 6
  year: 2025
  text: 20250603
  day: 3
PublicationDecade 2020
PublicationPlace United States
PublicationPlace_xml – name: United States
– name: San Francisco, CA USA
PublicationTitle PLoS computational biology
PublicationTitleAlternate PLoS Comput Biol
PublicationYear 2025
Publisher Public Library of Science
Public Library of Science (PLoS)
Publisher_xml – name: Public Library of Science
– name: Public Library of Science (PLoS)
References R Pérez-Tomás (pcbi.1013127.ref090) 2020; 12
CE Weber (pcbi.1013127.ref107) 2015; 34
TM Bui (pcbi.1013127.ref048) 2020; 108
RK Nimmakayala (pcbi.1013127.ref058) 2019; 1871
MM Wang (pcbi.1013127.ref100) 2023; 129
X Mao (pcbi.1013127.ref071) 2021; 20
EJ Kay (pcbi.1013127.ref045) 2021; 28
M Mandai (pcbi.1013127.ref079) 2016; 22
C Blank (pcbi.1013127.ref063) 2007; 56
P Jiang (pcbi.1013127.ref112) 2018; 24
K Hari (pcbi.1013127.ref016) 2023
Y Iwai (pcbi.1013127.ref040) 2002; 99
DE Johnson (pcbi.1013127.ref003) 2020; 6
A Zaitsev (pcbi.1013127.ref007) 2022; 40
S Dhar (pcbi.1013127.ref067) 2022; 10
Z Li (pcbi.1013127.ref095) 2023; 31
J Punt (pcbi.1013127.ref049) 2019
K-A Norton (pcbi.1013127.ref061) 2019; 7
Y Sunami (pcbi.1013127.ref070) 2022; 14
C Quek (pcbi.1013127.ref099) 2024; 43
M Archetti (pcbi.1013127.ref038) 2019; 19
M Otranto (pcbi.1013127.ref054) 2012; 6
MA Feitelson (pcbi.1013127.ref005) 2015; 35
V Richard (pcbi.1013127.ref033) 2023; 24
A Tosi (pcbi.1013127.ref115) 2022; 41
R Butti (pcbi.1013127.ref109) 2021; 40
F Tang (pcbi.1013127.ref029) 2009; 6
H Fazilaty (pcbi.1013127.ref014) 2019; 10
AZ Ayob (pcbi.1013127.ref059) 2018; 25
M Sharf (pcbi.1013127.ref011) 2022; 67
G Tanaka (pcbi.1013127.ref025) 2008; 237
G Tau (pcbi.1013127.ref046) 1999; 54
E Raeber (pcbi.1013127.ref105) 2022; 14
S Muhammad (pcbi.1013127.ref106) 2023; 22
J Gao (pcbi.1013127.ref078) 2016; 167
W Gu (pcbi.1013127.ref018) 2022; 12
M Španko (pcbi.1013127.ref072) 2021; 22
NY den Breems (pcbi.1013127.ref051) 2016; 390
MF Bachmann (pcbi.1013127.ref047) 2007; 8
EL Estephan (pcbi.1013127.ref102) 2024; 14
A Mantovani (pcbi.1013127.ref026) 2002; 23
X Chi (pcbi.1013127.ref068) 2023; 14
Y Jiang (pcbi.1013127.ref062) 2015; 6
CU Blank (pcbi.1013127.ref050) 2019; 19
AJ Luginbuhl (pcbi.1013127.ref097) 2022; 28
RM McLoughlin (pcbi.1013127.ref080) 2003; 112
PB Gupta (pcbi.1013127.ref030) 2011; 146
Y Li (pcbi.1013127.ref019) 2021; 19
C-F Qi (pcbi.1013127.ref073) 2009; 45
J Liu (pcbi.1013127.ref082) 2014; 45
Q Tang (pcbi.1013127.ref008) 2022; 13
C Zhang (pcbi.1013127.ref091) 2023; 14
SV Puram (pcbi.1013127.ref034) 2017; 171
D Barkley (pcbi.1013127.ref032) 2021; 31
K Fousek (pcbi.1013127.ref042) 2021; 219
J Albrengues (pcbi.1013127.ref069) 2015; 6
G Baggio (pcbi.1013127.ref012) 2021; 12
AJ Boutilier (pcbi.1013127.ref053) 2021; 22
M Pascual-García (pcbi.1013127.ref110) 2019; 10
J Pu (pcbi.1013127.ref052) 2021; 7
S Ghosh (pcbi.1013127.ref015) 2011; 44
GE Mahlbacher (pcbi.1013127.ref023) 2019; 469
JD Klement (pcbi.1013127.ref084) 2018; 128
MK Keck (pcbi.1013127.ref096) 2015; 21
L Martínez-Lostao (pcbi.1013127.ref064) 2015; 21
EA Bach (pcbi.1013127.ref076) 1997; 15
BL Hill (pcbi.1013127.ref093) 2023; 62
I Bozic (pcbi.1013127.ref022) 2013; 2
SD Cárdenas (pcbi.1013127.ref036) 2022; 8
E Sahai (pcbi.1013127.ref055) 2020; 20
G Comito (pcbi.1013127.ref087) 2019; 38
Y Togashi (pcbi.1013127.ref035) 2019; 16
D Petrik (pcbi.1013127.ref108) 2006; 24
M Pillai (pcbi.1013127.ref013) 2022; 25
H-F Kao (pcbi.1013127.ref009) 2019
A Sood (pcbi.1013127.ref028) 2016; 1
KE de Visser (pcbi.1013127.ref006) 2023; 41
K Liu (pcbi.1013127.ref081) 2021; 42
S-T Tsai (pcbi.1013127.ref085) 2015; 10
A Corthay (pcbi.1013127.ref066) 2009; 70
AT Pearson (pcbi.1013127.ref010) 2016; 73
JH Kearsley (pcbi.1013127.ref027) 1990; 61
JJ Patel (pcbi.1013127.ref037) 2020; 42
PJ Asif (pcbi.1013127.ref057) 2021; 13
T-A Lin (pcbi.1013127.ref075) 2020; 9
P Zhou (pcbi.1013127.ref017) 2021; 12
S Mayer (pcbi.1013127.ref094) 2023; 14
X Bao (pcbi.1013127.ref098) 2024; 5
EV Nikolaev (pcbi.1013127.ref114) 2016; 12
R Bright (pcbi.1013127.ref104) 2017; 40
X Pang (pcbi.1013127.ref083) 2019; 144
H Tao (pcbi.1013127.ref089) 2023; 14
A Psyrri (pcbi.1013127.ref020) 2013; 8
P Economopoulou (pcbi.1013127.ref002) 2019; 9
Z Li (pcbi.1013127.ref088) 2023; 10
CJ Workman (pcbi.1013127.ref065) 2009; 66
D Jorgovanovic (pcbi.1013127.ref077) 2020; 8
Z Xiao (pcbi.1013127.ref103) 2023; 14
ME Sehl (pcbi.1013127.ref031) 2015; 10
Y Zheng (pcbi.1013127.ref041) 2019; 18
AS Halkola (pcbi.1013127.ref024) 2020; 488
Y Kariya (pcbi.1013127.ref043) 2022; 2
J Wang (pcbi.1013127.ref074) 2023; 31
A Celetti (pcbi.1013127.ref111) 2005; 11
A Brown (pcbi.1013127.ref113) 2023; 14
H Raskov (pcbi.1013127.ref039) 2021; 124
A Bagaev (pcbi.1013127.ref004) 2021; 39
C Zhang (pcbi.1013127.ref044) 2023; 14
J Hedberg (pcbi.1013127.ref001) 2015; 2
J Zhadong (pcbi.1013127.ref056) 2021; 9
Y Shiravand (pcbi.1013127.ref092) 2022; 29
JL Farlow (pcbi.1013127.ref101) 2021; 120
C Raimondi (pcbi.1013127.ref060) 2017; 6
HR Moorman (pcbi.1013127.ref086) 2022; 11
GW Swan (pcbi.1013127.ref021) 1990; 101
39386511 - bioRxiv. 2024 Sep 27:2024.09.26.615149. doi: 10.1101/2024.09.26.615149.
References_xml – volume: 16
  start-page: 356
  issue: 6
  year: 2019
  ident: pcbi.1013127.ref035
  article-title: Regulatory T cells in cancer immunosuppression - implications for anticancer therapy
  publication-title: Nat Rev Clin Oncol
  doi: 10.1038/s41571-019-0175-7
– volume: 14
  start-page: 5110
  issue: 1
  year: 2023
  ident: pcbi.1013127.ref103
  article-title: Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors
  publication-title: Nat Commun
  doi: 10.1038/s41467-023-40850-5
– year: 2023
  ident: pcbi.1013127.ref016
  article-title: Low dimensionality of phenotypic space as an emergent property of coordinated teams in biological regulatory networks
  publication-title: bioRxiv
– volume: 99
  start-page: 12293
  issue: 19
  year: 2002
  ident: pcbi.1013127.ref040
  article-title: Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade
  publication-title: Proc Natl Acad Sci U S A
  doi: 10.1073/pnas.192461099
– volume-title: Kuby immunology
  year: 2019
  ident: pcbi.1013127.ref049
– volume: 11
  start-page: 8019
  issue: 22
  year: 2005
  ident: pcbi.1013127.ref111
  article-title: Overexpression of the cytokine osteopontin identifies aggressive laryngeal squamous cell carcinomas and enhances carcinoma cell proliferation and invasiveness
  publication-title: Clin Cancer Res
  doi: 10.1158/1078-0432.CCR-05-0641
– volume: 10
  issue: 11
  year: 2015
  ident: pcbi.1013127.ref085
  article-title: ICAM1 is a potential cancer stem cell marker of esophageal squamous cell carcinoma
  publication-title: PLoS One
– volume: 31
  start-page: 100740
  year: 2023
  ident: pcbi.1013127.ref095
  article-title: Targeting the lactic acid metabolic pathway for antitumor therapy
  publication-title: Mol Ther Oncolytics
  doi: 10.1016/j.omto.2023.100740
– volume: 7
  start-page: 37
  issue: 1
  year: 2019
  ident: pcbi.1013127.ref061
  article-title: Multiscale Agent-Based and Hybrid Modeling of the Tumor Immune Microenvironment
  publication-title: Processes (Basel)
  doi: 10.3390/pr7010037
– volume: 14
  start-page: 5810
  issue: 1
  year: 2023
  ident: pcbi.1013127.ref094
  article-title: The tumor microenvironment shows a hierarchy of cell-cell interactions dominated by fibroblasts
  publication-title: Nat Commun
  doi: 10.1038/s41467-023-41518-w
– volume: 2
  year: 2013
  ident: pcbi.1013127.ref022
  article-title: Evolutionary dynamics of cancer in response to targeted combination therapy
  publication-title: Elife
  doi: 10.7554/eLife.00747
– volume: 6
  start-page: 203
  issue: 3
  year: 2012
  ident: pcbi.1013127.ref054
  article-title: The role of the myofibroblast in tumor stroma remodeling
  publication-title: Cell Adh Migr
  doi: 10.4161/cam.20377
– volume: 12
  start-page: 1
  year: 2021
  ident: pcbi.1013127.ref017
  article-title: Dissecting transition cells from single-cell transcriptome data through multiscale stochastic dynamics
  publication-title: Nat Commun
  doi: 10.1038/s41467-021-25548-w
– volume: 2
  start-page: 491
  year: 2015
  ident: pcbi.1013127.ref001
  article-title: The molecular pathogenesis of head and neck cancer in
  publication-title: The Molecular Basis of Cancer
  doi: 10.1016/B978-1-4557-4066-6.00033-0
– volume: 129
  start-page: 1212
  issue: 8
  year: 2023
  ident: pcbi.1013127.ref100
  article-title: Resistance to immune checkpoint therapies by tumour-induced T-cell desertification and exclusion: key mechanisms, prognostication and new therapeutic opportunities
  publication-title: Br J Cancer
  doi: 10.1038/s41416-023-02361-4
– volume: 10
  start-page: 5115
  issue: 1
  year: 2019
  ident: pcbi.1013127.ref014
  article-title: A gene regulatory network to control EMT programs in development and disease
  publication-title: Nat Commun
  doi: 10.1038/s41467-019-13091-8
– volume: 8
  start-page: 246
  year: 2013
  ident: pcbi.1013127.ref020
  article-title: Molecular pathways in head and neck cancer: Egfr, pi3k, and more
  publication-title: Am Soc Clin Oncol
– volume: 28
  start-page: 915
  issue: 5
  year: 2022
  ident: pcbi.1013127.ref097
  article-title: Tadalafil enhances immune signatures in response to neoadjuvant nivolumab in resectable head and neck squamous cell carcinoma
  publication-title: Clin Cancer Res
  doi: 10.1158/1078-0432.CCR-21-1816
– volume: 24
  year: 2023
  ident: pcbi.1013127.ref033
  article-title: Cell state transitions and phenotypic heterogeneity in luminal breast cancer implicating micro-RNAs as potential regulators
  publication-title: Int J Mol Sci
  doi: 10.3390/ijms24043497
– volume: 171
  issue: 7
  year: 2017
  ident: pcbi.1013127.ref034
  article-title: Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer
  publication-title: Cell
  doi: 10.1016/j.cell.2017.10.044
– volume: 22
  start-page: 1
  year: 2021
  ident: pcbi.1013127.ref053
  article-title: Macrophage polarization states in the tumor microenvironment
  publication-title: Int J Mol Sci
  doi: 10.3390/ijms22136995
– volume: 70
  start-page: 326
  issue: 4
  year: 2009
  ident: pcbi.1013127.ref066
  article-title: How do regulatory T cells work?
  publication-title: Scand J Immunol
  doi: 10.1111/j.1365-3083.2009.02308.x
– volume: 488
  start-page: 110136
  year: 2020
  ident: pcbi.1013127.ref024
  article-title: Modelling of killer T-cell and cancer cell subpopulation dynamics under immuno- and chemotherapies
  publication-title: J Theor Biol
  doi: 10.1016/j.jtbi.2019.110136
– volume: 8
  start-page: 1142
  issue: 12
  year: 2007
  ident: pcbi.1013127.ref047
  article-title: Interleukin 2: from immunostimulation to immunoregulation and back again
  publication-title: EMBO Rep
  doi: 10.1038/sj.embor.7401099
– volume: 108
  start-page: 787
  year: 2020
  ident: pcbi.1013127.ref048
  article-title: ICAM-1: A master regulator of cellular responses in inflammation, injury resolution, and tumorigenesis
  publication-title: J Leukoc Biol
  doi: 10.1002/JLB.2MR0220-549R
– volume: 469
  start-page: 47
  year: 2019
  ident: pcbi.1013127.ref023
  article-title: Mathematical modeling of tumor-immune cell interactions
  publication-title: J Theor Biol
  doi: 10.1016/j.jtbi.2019.03.002
– volume: 10
  start-page: 2416
  issue: 1
  year: 2019
  ident: pcbi.1013127.ref110
  article-title: LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy
  publication-title: Nat Commun
  doi: 10.1038/s41467-019-10369-9
– volume: 44
  start-page: 192
  issue: 2
  year: 2011
  ident: pcbi.1013127.ref015
  article-title: Mathematical model of the role of intercellular signalling in intercellular cooperation during tumorigenesis
  publication-title: Cell Prolif
  doi: 10.1111/j.1365-2184.2011.00739.x
– volume: 12
  start-page: 3244
  issue: 11
  year: 2020
  ident: pcbi.1013127.ref090
  article-title: Lactate in the tumor microenvironment: an essential molecule in cancer progression and treatment
  publication-title: Cancers (Basel)
  doi: 10.3390/cancers12113244
– volume: 43
  start-page: 114392
  issue: 7
  year: 2024
  ident: pcbi.1013127.ref099
  article-title: Single-cell spatial multiomics reveals tumor microenvironment vulnerabilities in cancer resistance to immunotherapy
  publication-title: Cell Rep
  doi: 10.1016/j.celrep.2024.114392
– volume: 13
  start-page: 964442
  year: 2022
  ident: pcbi.1013127.ref008
  article-title: The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers
  publication-title: Front Immunol
  doi: 10.3389/fimmu.2022.964442
– volume: 12
  start-page: 1
  year: 2022
  ident: pcbi.1013127.ref018
  article-title: The role of feedback loops in targeted therapy for pancreatic cancer
  publication-title: Front. Oncol
– volume: 73
  start-page: 3279
  issue: 17
  year: 2016
  ident: pcbi.1013127.ref010
  article-title: Modeling head and neck cancer stem cell-mediated tumorigenesis
  publication-title: Cell Mol Life Sci
  doi: 10.1007/s00018-016-2226-x
– volume: 9
  start-page: 1
  year: 2021
  ident: pcbi.1013127.ref056
  article-title: Cancer-associated fibroblast-derived interleukin-8 promotes ovarian cancer cell stemness and malignancy through the notch3-mediated signaling
  publication-title: Front Cell Dev Biol
– volume: 13
  start-page: 4720
  issue: 18
  year: 2021
  ident: pcbi.1013127.ref057
  article-title: The Role of Cancer-Associated Fibroblasts in Cancer Invasion and Metastasis
  publication-title: Cancers (Basel)
  doi: 10.3390/cancers13184720
– volume: 6
  issue: 6
  year: 2015
  ident: pcbi.1013127.ref062
  article-title: T-cell exhaustion in the tumor microenvironment
  publication-title: Cell Death Dis
  doi: 10.1038/cddis.2015.162
– volume: 31
  start-page: 1719
  issue: 10
  year: 2021
  ident: pcbi.1013127.ref032
  article-title: Cancer cell states and emergent properties of the dynamic tumor system
  publication-title: Genome Res
  doi: 10.1101/gr.275308.121
– volume: 28
  start-page: 100377
  year: 2021
  ident: pcbi.1013127.ref045
  article-title: Metabolic pathways fuelling protumourigenic cancer-associated fibroblast functions
  publication-title: Current Opinion in Systems Biology
  doi: 10.1016/j.coisb.2021.100377
– volume: 34
  start-page: 4821
  issue: 37
  year: 2015
  ident: pcbi.1013127.ref107
  article-title: Osteopontin mediates an MZF1-TGF-β1-dependent transformation of mesenchymal stem cells into cancer-associated fibroblasts in breast cancer
  publication-title: Oncogene
  doi: 10.1038/onc.2014.410
– volume: 41
  start-page: 279
  issue: 1
  year: 2022
  ident: pcbi.1013127.ref115
  article-title: The immune microenvironment of HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma: a multiparametric quantitative and spatial analysis unveils a rationale to target treatment-naïve tumors with immune checkpoint inhibitors
  publication-title: J Exp Clin Cancer Res
  doi: 10.1186/s13046-022-02481-4
– volume: 14
  start-page: 1104771
  year: 2023
  ident: pcbi.1013127.ref068
  article-title: T-cell exhaustion and stemness in antitumor immunity: Characteristics, mechanisms, and implications
  publication-title: Front Immunol
  doi: 10.3389/fimmu.2023.1104771
– volume: 67
  start-page: 754
  issue: 2
  year: 2022
  ident: pcbi.1013127.ref011
  article-title: Model-free practical cooperative control for diffusively coupled systems
  publication-title: IEEE Trans Automat Contr
  doi: 10.1109/TAC.2021.3056582
– volume: 167
  issue: 2
  year: 2016
  ident: pcbi.1013127.ref078
  article-title: Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy
  publication-title: Cell
– volume: 21
  start-page: 870
  issue: 4
  year: 2015
  ident: pcbi.1013127.ref096
  article-title: Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes
  publication-title: Clin Cancer Res
  doi: 10.1158/1078-0432.CCR-14-2481
– volume: 22
  start-page: 121
  issue: 1
  year: 2023
  ident: pcbi.1013127.ref106
  article-title: Reigniting hope in cancer treatment: the promise and pitfalls of IL-2 and IL-2R targeting strategies
  publication-title: Mol Cancer
  doi: 10.1186/s12943-023-01826-7
– volume: 19
  start-page: 665
  year: 2019
  ident: pcbi.1013127.ref050
  article-title: Defining ‘T cell exhaustion’
  publication-title: Nat Rev Immunol
  doi: 10.1038/s41577-019-0221-9
– volume: 8
  start-page: 49
  year: 2020
  ident: pcbi.1013127.ref077
  article-title: Roles of IFN-γ in tumor progression and regression: a review
  publication-title: Biomark Res
  doi: 10.1186/s40364-020-00228-x
– volume: 39
  issue: 6
  year: 2021
  ident: pcbi.1013127.ref004
  article-title: Conserved pan-cancer microenvironment subtypes predict response to immunotherapy
  publication-title: Cancer Cell
  doi: 10.1016/j.ccell.2021.04.014
– volume: 41
  start-page: 374
  issue: 3
  year: 2023
  ident: pcbi.1013127.ref006
  article-title: The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth
  publication-title: Cancer Cell
  doi: 10.1016/j.ccell.2023.02.016
– volume: 390
  start-page: 23
  year: 2016
  ident: pcbi.1013127.ref051
  article-title: The re-polarisation of M2 and M1 macrophages and its role on cancer outcomes
  publication-title: J Theor Biol
  doi: 10.1016/j.jtbi.2015.10.034
– volume: 14
  year: 2023
  ident: pcbi.1013127.ref091
  article-title: CAFs orchestrates tumor immune microenvironment—a new target in cancer therapy?
  publication-title: Frontiers in Pharmacology
– volume: 14
  start-page: 1
  year: 2022
  ident: pcbi.1013127.ref105
  article-title: Interleukin-2–based therapies in cancer
  publication-title: Sci Trans Med
  doi: 10.1126/scitranslmed.abo5409
– volume: 18
  start-page: 5399
  issue: 5
  year: 2019
  ident: pcbi.1013127.ref041
  article-title: PD-L1 expression levels on tumor cells affect their immunosuppressive activity
  publication-title: Oncol Lett
– volume: 14
  start-page: 2139
  issue: 22
  year: 2023
  ident: pcbi.1013127.ref044
  article-title: Lactate secreted by esophageal cancer cells induces M2 macrophage polarization via the AKT/ERK pathway
  publication-title: Thorac Cancer
  doi: 10.1111/1759-7714.14998
– volume: 146
  start-page: 633
  issue: 4
  year: 2011
  ident: pcbi.1013127.ref030
  article-title: Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells
  publication-title: Cell
  doi: 10.1016/j.cell.2011.07.026
– volume: 25
  start-page: 105499
  issue: 12
  year: 2022
  ident: pcbi.1013127.ref013
  article-title: Quantitative landscapes reveal trajectories of cell-state transitions associated with drug resistance in melanoma
  publication-title: iScience
  doi: 10.1016/j.isci.2022.105499
– volume: 8
  start-page: 32
  issue: 1
  year: 2022
  ident: pcbi.1013127.ref036
  article-title: Model-informed experimental design recommendations for distinguishing intrinsic and acquired targeted therapeutic resistance in head and neck cancer
  publication-title: NPJ Syst Biol Appl
  doi: 10.1038/s41540-022-00244-7
– volume: 54
  start-page: 1233
  issue: 12
  year: 1999
  ident: pcbi.1013127.ref046
  article-title: Biologic functions of the IFN-gamma receptors
  publication-title: Allergy
  doi: 10.1034/j.1398-9995.1999.00099.x
– volume: 9
  start-page: 295
  issue: 2
  year: 2020
  ident: pcbi.1013127.ref075
  article-title: Role and Mechanism of LIF in oral squamous cell carcinoma progression
  publication-title: J Clin Med
  doi: 10.3390/jcm9020295
– volume: 15
  start-page: 563
  year: 1997
  ident: pcbi.1013127.ref076
  article-title: The IFN gamma receptor: a paradigm for cytokine receptor signaling
  publication-title: Annu Rev Immunol
  doi: 10.1146/annurev.immunol.15.1.563
– volume: 61
  start-page: 821
  issue: 6
  year: 1990
  ident: pcbi.1013127.ref027
  article-title: An immunohistochemical assessment of cellular proliferation markers in head and neck squamous cell cancers
  publication-title: Br J Cancer
  doi: 10.1038/bjc.1990.184
– volume: 12
  start-page: 1429
  issue: 1
  year: 2021
  ident: pcbi.1013127.ref012
  article-title: Data-driven control of complex networks
  publication-title: Nat Commun
  doi: 10.1038/s41467-021-21554-0
– volume: 22
  start-page: 11027
  issue: 20
  year: 2021
  ident: pcbi.1013127.ref072
  article-title: IL-6 in the ecosystem of head and neck cancer: possible therapeutic perspectives
  publication-title: Int J Mol Sci
  doi: 10.3390/ijms222011027
– volume: 62
  start-page: 1428
  year: 2023
  ident: pcbi.1013127.ref093
  article-title: Il-8 correlates with nonresponse to neoadjuvant nivolumab in HPV positive HNSCC via a potential extracellular vesicle mir-146a mediated mechanism
  publication-title: Mol. Carcinog
  doi: 10.1002/mc.23587
– volume: 1
  issue: 6
  year: 2016
  ident: pcbi.1013127.ref028
  article-title: Multiplexed immunofluorescence delineates proteomic cancer cell states associated with metabolism
  publication-title: JCI Insight
  doi: 10.1172/jci.insight.87030
– volume: 25
  start-page: 1
  year: 2018
  ident: pcbi.1013127.ref059
  article-title: Cancer stem cells as key drivers of tumour progression
  publication-title: J Biomed Sci
– volume: 144
  start-page: 235
  year: 2019
  ident: pcbi.1013127.ref083
  article-title: Osteopontin as a multifaceted driver of bone metastasis and drug resistance
  publication-title: Pharmacol Res
  doi: 10.1016/j.phrs.2019.04.030
– start-page: 4
  year: 2019
  ident: pcbi.1013127.ref009
  article-title: Immune checkpoint inhibitors for head and neck squamous cell carcinoma: Current landscape and future directions
  publication-title: Head Neck
  doi: 10.1002/hed.25930
– volume: 38
  start-page: 3681
  issue: 19
  year: 2019
  ident: pcbi.1013127.ref087
  article-title: Lactate modulates CD4+ T-cell polarization and induces an immunosuppressive environment, which sustains prostate carcinoma progression via TLR8/miR21 axis
  publication-title: Oncogene
  doi: 10.1038/s41388-019-0688-7
– volume: 124
  start-page: 359
  issue: 2
  year: 2021
  ident: pcbi.1013127.ref039
  article-title: Cytotoxic CD8+ T cells in cancer and cancer immunotherapy
  publication-title: Br J Cancer
  doi: 10.1038/s41416-020-01048-4
– volume: 9
  start-page: 827
  year: 2019
  ident: pcbi.1013127.ref002
  article-title: Diagnostic tumor markers in Head and Neck Squamous Cell Carcinoma (HNSCC) in the clinical setting
  publication-title: Front Oncol
  doi: 10.3389/fonc.2019.00827
– volume: 21
  start-page: 5047
  issue: 22
  year: 2015
  ident: pcbi.1013127.ref064
  article-title: How do cytotoxic lymphocytes kill cancer cells?
  publication-title: Clin Cancer Res
  doi: 10.1158/1078-0432.CCR-15-0685
– volume: 19
  start-page: 110
  issue: 2
  year: 2019
  ident: pcbi.1013127.ref038
  article-title: Cooperation among cancer cells: applying game theory to cancer
  publication-title: Nat Rev Cancer
  doi: 10.1038/s41568-018-0083-7
– volume: 45
  start-page: 62
  issue: 1
  year: 2009
  ident: pcbi.1013127.ref073
  article-title: Differential expression of IRF8 in subsets of macrophages and dendritic cells and effects of IRF8 deficiency on splenic B cell and macrophage compartments
  publication-title: Immunol Res
  doi: 10.1007/s12026-008-8032-2
– volume: 42
  start-page: 774
  issue: 4
  year: 2020
  ident: pcbi.1013127.ref037
  article-title: Impact of PD-L1 expression and human papillomavirus status in anti-PD1/PDL1 immunotherapy for head and neck squamous cell carcinoma-Systematic review and meta-analysis
  publication-title: Head Neck
  doi: 10.1002/hed.26036
– volume: 14
  start-page: 1208870
  year: 2023
  ident: pcbi.1013127.ref089
  article-title: Unveiling the veil of lactate in tumor-associated macrophages: a successful strategy for immunometabolic therapy
  publication-title: Front Immunol
  doi: 10.3389/fimmu.2023.1208870
– volume: 6
  start-page: 1
  year: 2017
  ident: pcbi.1013127.ref060
  article-title: PD-L1 and epithelial-mesenchymal transition in circulating tumor cells from non-small cell lung cancer patients: A molecular shield to evade immune system?
  publication-title: OncoImmunology
  doi: 10.1080/2162402X.2017.1315488
– volume: 40
  start-page: 21
  issue: 1
  year: 2017
  ident: pcbi.1013127.ref104
  article-title: Clinical response rates from interleukin-2 therapy for metastatic melanoma over 30 years’ experience: a meta-analysis of 3312 patients
  publication-title: J Immunother
  doi: 10.1097/CJI.0000000000000149
– volume: 6
  start-page: 377
  issue: 5
  year: 2009
  ident: pcbi.1013127.ref029
  article-title: mRNA-Seq whole-transcriptome analysis of a single cell
  publication-title: Nat Methods
  doi: 10.1038/nmeth.1315
– volume: 10
  start-page: 1113739
  year: 2023
  ident: pcbi.1013127.ref088
  article-title: Lactate in the tumor microenvironment: A rising star for targeted tumor therapy
  publication-title: Front Nutr
  doi: 10.3389/fnut.2023.1113739
– volume: 42
  start-page: 414
  issue: 3
  year: 2021
  ident: pcbi.1013127.ref081
  article-title: RUNX1 promotes MAPK signaling to increase tumor progression and metastasis via OPN in head and neck cancer
  publication-title: Carcinogenesis
  doi: 10.1093/carcin/bgaa116
– volume: 24
  start-page: 1550
  issue: 10
  year: 2018
  ident: pcbi.1013127.ref112
  article-title: Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response
  publication-title: Nat Med
  doi: 10.1038/s41591-018-0136-1
– volume: 23
  start-page: 549
  issue: 11
  year: 2002
  ident: pcbi.1013127.ref026
  article-title: Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes
  publication-title: Trends Immunol
  doi: 10.1016/S1471-4906(02)02302-5
– volume: 128
  start-page: 5549
  issue: 12
  year: 2018
  ident: pcbi.1013127.ref084
  article-title: An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion
  publication-title: J Clin Invest
  doi: 10.1172/JCI123360
– volume: 237
  start-page: 2616
  issue: 20
  year: 2008
  ident: pcbi.1013127.ref025
  article-title: Bifurcation analysis on a hybrid systems model of intermittent hormonal therapy for prostate cancer
  publication-title: Physica D: Nonlinear Phenomena
  doi: 10.1016/j.physd.2008.03.044
– volume: 20
  start-page: 174
  issue: 3
  year: 2020
  ident: pcbi.1013127.ref055
  article-title: A framework for advancing our understanding of cancer-associated fibroblasts
  publication-title: Nat Rev Cancer
  doi: 10.1038/s41568-019-0238-1
– volume: 66
  start-page: 2603
  issue: 16
  year: 2009
  ident: pcbi.1013127.ref065
  article-title: The development and function of regulatory T cells
  publication-title: Cell Mol Life Sci
  doi: 10.1007/s00018-009-0026-2
– volume: 22
  start-page: 2329
  issue: 10
  year: 2016
  ident: pcbi.1013127.ref079
  article-title: Dual Faces of IFNγ in cancer progression: a role of PD-L1 induction in the determination of pro- and antitumor immunity
  publication-title: Clin Cancer Res
  doi: 10.1158/1078-0432.CCR-16-0224
– volume: 12
  start-page: 1
  year: 2016
  ident: pcbi.1013127.ref114
  article-title: Quorum-sensing synchronization of synthetic toggle switches: a design based on monotone dynamical systems theory
  publication-title: PLoS Comput Biol
  doi: 10.1371/journal.pcbi.1004881
– volume: 14
  start-page: 1
  year: 2024
  ident: pcbi.1013127.ref102
  article-title: Altered extracellular matrix correlates with an immunosuppressive tumor microenvironment and disease progression in younger adults with oral cavity squamous cell carcinoma
  publication-title: Front Oncol
  doi: 10.3389/fonc.2024.1412212
– volume: 2
  start-page: 419
  issue: 3
  year: 2022
  ident: pcbi.1013127.ref043
  article-title: Osteopontin in cancer: mechanisms and therapeutic targets
  publication-title: IJTM
  doi: 10.3390/ijtm2030033
– volume: 14
  start-page: 1212749
  year: 2023
  ident: pcbi.1013127.ref113
  article-title: Mathematical modeling clarifies the paracrine roles of insulin and glucagon on the glucose-stimulated hormonal secretion of pancreatic alpha- and beta-cells
  publication-title: Front Endocrinol (Lausanne)
  doi: 10.3389/fendo.2023.1212749
– volume: 40
  start-page: 2002
  issue: 11
  year: 2021
  ident: pcbi.1013127.ref109
  article-title: Tumor-derived osteopontin drives the resident fibroblast to myofibroblast differentiation through Twist1 to promote breast cancer progression
  publication-title: Oncogene
  doi: 10.1038/s41388-021-01663-2
– volume: 19
  start-page: 19
  issue: 1
  year: 2021
  ident: pcbi.1013127.ref019
  article-title: Drug resistance and Cancer stem cells
  publication-title: Cell Commun Signal
  doi: 10.1186/s12964-020-00627-5
– volume: 45
  start-page: 282
  issue: 1
  year: 2014
  ident: pcbi.1013127.ref082
  article-title: Osteopontin promotes the progression of gastric cancer through the NF-κB pathway regulated by the MAPK and PI3K
  publication-title: Int J Oncol
  doi: 10.3892/ijo.2014.2393
– volume: 5
  start-page: 101399
  issue: 2
  year: 2024
  ident: pcbi.1013127.ref098
  article-title: A multiomics analysis-assisted deep learning model identifies a macrophage-oriented module as a potential therapeutic target in colorectal cancer
  publication-title: Cell Rep Med
  doi: 10.1016/j.xcrm.2024.101399
– volume: 29
  start-page: 3044
  issue: 5
  year: 2022
  ident: pcbi.1013127.ref092
  article-title: Immune checkpoint inhibitors in cancer therapy
  publication-title: Curr Oncol
  doi: 10.3390/curroncol29050247
– volume: 6
  start-page: 92
  issue: 1
  year: 2020
  ident: pcbi.1013127.ref003
  article-title: Head and neck squamous cell carcinoma
  publication-title: Nat Rev Dis Primers
  doi: 10.1038/s41572-020-00224-3
– volume: 56
  start-page: 739
  issue: 5
  year: 2007
  ident: pcbi.1013127.ref063
  article-title: Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion
  publication-title: Cancer Immunol Immunother
  doi: 10.1007/s00262-006-0272-1
– volume: 10
  start-page: 1497
  year: 2022
  ident: pcbi.1013127.ref067
  article-title: 1439 terminally exhausted cd8 tils promote aggressive cancer stem cells while concurrently evading anti pd1 therapy
  publication-title: J for Immun Th Cancer
– volume: 219
  start-page: 107692
  year: 2021
  ident: pcbi.1013127.ref042
  article-title: Interleukin-8: A chemokine at the intersection of cancer plasticity, angiogenesis, and immune suppression
  publication-title: Pharmacol Ther
  doi: 10.1016/j.pharmthera.2020.107692
– volume: 120
  start-page: 105420
  year: 2021
  ident: pcbi.1013127.ref101
  article-title: Immune deserts in head and neck squamous cell carcinoma: A review of challenges and opportunities for modulating the tumor immune microenvironment
  publication-title: Oral Oncol
  doi: 10.1016/j.oraloncology.2021.105420
– volume: 6
  start-page: 10204
  year: 2015
  ident: pcbi.1013127.ref069
  article-title: Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts
  publication-title: Nat Commun
  doi: 10.1038/ncomms10204
– volume: 7
  start-page: 182
  issue: 1
  year: 2021
  ident: pcbi.1013127.ref052
  article-title: M2 macrophage-derived extracellular vesicles facilitate CD8+T cell exhaustion in hepatocellular carcinoma via the miR-21-5p/YOD1/YAP/β-catenin pathway
  publication-title: Cell Death Discov
  doi: 10.1038/s41420-021-00556-3
– volume: 11
  start-page: 2630
  issue: 17
  year: 2022
  ident: pcbi.1013127.ref086
  article-title: IRF8: mechanism of action and health implications
  publication-title: Cells
  doi: 10.3390/cells11172630
– volume: 40
  issue: 8
  year: 2022
  ident: pcbi.1013127.ref007
  article-title: Precise reconstruction of the TME using bulk RNA-seq and a machine learning algorithm trained on artificial transcriptomes
  publication-title: Cancer Cell
  doi: 10.1016/j.ccell.2022.07.006
– volume: 101
  start-page: 237
  issue: 2
  year: 1990
  ident: pcbi.1013127.ref021
  article-title: Role of optimal control theory in cancer chemotherapy
  publication-title: Math Biosci
  doi: 10.1016/0025-5564(90)90021-P
– volume: 112
  start-page: 598
  issue: 4
  year: 2003
  ident: pcbi.1013127.ref080
  article-title: Interplay between IFN-gamma and IL-6 signaling governs neutrophil trafficking and apoptosis during acute inflammation
  publication-title: J Clin Invest
  doi: 10.1172/JCI17129
– volume: 35
  start-page: 25
  year: 2015
  ident: pcbi.1013127.ref005
  article-title: Sustained proliferation in cancer: mechanisms and novel therapeutic targets
  publication-title: Semin Cancer Biol
  doi: 10.1016/j.semcancer.2015.02.006
– volume: 20
  start-page: 131
  issue: 1
  year: 2021
  ident: pcbi.1013127.ref071
  article-title: Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives
  publication-title: Mol Cancer
  doi: 10.1186/s12943-021-01428-1
– volume: 24
  start-page: 5291
  year: 2006
  ident: pcbi.1013127.ref108
  article-title: Plasma osteopontin is an independent prognostic marker for head and neck cancers
  publication-title: J Clin Oncol
  doi: 10.1200/JCO.2006.06.8627
– volume: 14
  start-page: 744
  issue: 3
  year: 2022
  ident: pcbi.1013127.ref070
  article-title: Cancer-associated fibroblasts and tumor cells in pancreatic cancer microenvironment and metastasis: paracrine regulators, reciprocation and exosomes
  publication-title: Cancers (Basel)
  doi: 10.3390/cancers14030744
– volume: 10
  issue: 9
  year: 2015
  ident: pcbi.1013127.ref031
  article-title: Modeling of cancer stem cell state transitions predicts therapeutic response
  publication-title: PLoS One
– volume: 31
  start-page: 331
  issue: 2
  year: 2023
  ident: pcbi.1013127.ref074
  article-title: Leukemia inhibitory factor, a double-edged sword with therapeutic implications in human diseases
  publication-title: Mol Ther
  doi: 10.1016/j.ymthe.2022.12.016
– volume: 1871
  start-page: 50
  year: 2019
  ident: pcbi.1013127.ref058
  article-title: Unraveling the journey of cancer stem cells from origin to metastasis
  publication-title: Biochimica et Biophys. Acta (BBA) - Rev. on Cancer
  doi: 10.1016/j.bbcan.2018.10.006
– reference: 39386511 - bioRxiv. 2024 Sep 27:2024.09.26.615149. doi: 10.1101/2024.09.26.615149.
SSID ssj0035896
Score 2.4645042
Snippet Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune...
SourceID doaj
pubmedcentral
proquest
gale
pubmed
crossref
SourceType Open Website
Open Access Repository
Aggregation Database
Index Database
StartPage e1013127
SubjectTerms Biology and Life Sciences
Care and treatment
Computational Biology
Computer Simulation
Ecology and Environmental Sciences
Head and Neck Neoplasms - immunology
Head and Neck Neoplasms - pathology
Head and Neck Neoplasms - therapy
Humans
Immune Checkpoint Inhibitors - therapeutic use
Immunotherapy
Immunotherapy - methods
Medicine and Health Sciences
Methods
Models, Biological
Prognosis
Squamous cell carcinoma
Squamous Cell Carcinoma of Head and Neck - immunology
Squamous Cell Carcinoma of Head and Neck - pathology
Squamous Cell Carcinoma of Head and Neck - therapy
Tumor Microenvironment - immunology
SummonAdditionalLinks – databaseName: DOAJ Directory of Open Access Journals
  dbid: DOA
  link: http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwrV1Lb9QwELZQJSQuiDeBggxC4hSaxHYc97YgqoIEB2ilvVl-Lqtqk9LdHPpT-LedcbJVIg5cuK4daccztmfGM99HyLuqqa3h3OdOOZ5zKXjexAL2FWKnSPARSo_5jm_f69Nz_nUplhOqL6wJG-CBh4U7klUTufUxcud5qJ2C-x3cAi9YVRrPE9h2oYp9MDWcwUw0iZkLSXFyyfhybJpjsjwadfTh0tk1xq4sMcpMLqWE3f_3CT25oublk5P76OQBuT86knQxCPCQ3AntI3J3oJa8fkz-nPWb7opusN5u0sxGV4lbd0vB76NYm9V2CNRMU8cv1kLRLtI19oyMnVnXFLxaCie2pzCFtsFd0O3v3mDGgGLWnzpkI2q7jTmmC-oSScSYYKSJZidf9Wsf8PMB_uQJOT_5fPbpNB9pGHInKrnLRW0lvv5V0jSF8tLbaIKy0nMRg7GNkUUwxpSWQTBWVI47rgJ3rhYycGUVe0oO2q4Nzwn1rgi-UQHCSsmj8iaqICBArz2cucxWGcn3etCXA9qGTk9uEqKUYV016k2PesvIR1TW7VzEyk4_gAXp0YL0vywoI29R1RrRMFost1mZfrvVX37-0AvwzmpsvxUZeT9Oih0o3ZmxewHkQgCt2czD2UzYrm42_GZvURqHsMatDaAzDX9HCIh1lMrIs8HCbgXj-H7NBAjczGxvJvl8pF3_SmjhZVXWENezF_9jrV6SexUSIGMaih2Sg91VH16BV7azr9MGvAEI0Tke
  priority: 102
  providerName: Directory of Open Access Journals
Title Tumor microenvironment governs the prognostic landscape of immunotherapy for head and neck squamous cell carcinoma: A computational model-guided analysis
URI https://www.ncbi.nlm.nih.gov/pubmed/40460357
https://www.proquest.com/docview/3215572999
https://pubmed.ncbi.nlm.nih.gov/PMC12162103
https://doaj.org/article/728f4bdff4cd4e6c9435095d5321ad46
Volume 21
hasFullText 1
inHoldings 1
isFullTextHit
isPrint
link http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwjV1bi9NAFB72guCLeN_urmUUwacsTTKTyQgirW5dBRdZt9C3YW6pRZvs9gL2p_hvPWeSlgYVfGlp5yTt5MyZOfePkJdJnhnNmIustCxigrMoL3ogV9g7RYCOEDv0d3y-zC5G7NOYj_fIBrO1eYCLv5p2iCc1mv84-3m7fgsC_yagNoh4c9HZjTVTtEbTOBH75DBEjDCZj23jCinPA2IXguVEAj41xXT_ukvrsAo9_f_cuXeOrnZa5c45NbxP7jUKJu3XK-IB2fPlQ3KnhpxcPyK_rlezak5nmIe3U-RGJwFzd0FBH6SYs1VW2MCZhkpgzJGiVUGnWEvSVGytKWi7FHZyR4GElt5-p4vblUZPAsVoALWIUlRWM_2a9qkN4BGN45EG-J1ospo6j5fXbVEek9Hw_PrdRdTAM0SWJ2IZ8cwIjAomQuc96YQzhfbSCMd44bXJteh5rXVsUjDSeolllknPrM248EwamT4hB2VV-iNCne15l0sP5qZghXS6kJ6D4Z452ItTk3RItOGDuqm7cKgQihNgvdTPVSHfVMO3Dhkgs7a02EM7fFHNJ6oRSSWSvGDGFQWzjvnMStAcQeF0PE1i7VjWIS-Q1Qq7ZJSYhjPRq8VCffx6pfqgtWVYlss75FVDVFTAdKubqgaYFzbWalGetihBjG1r-PlmRSkcwty30gPPFPwdzsEGkrJDntYrbDsxhnHtlMOE89baa828PVJOv4Uu4nESZ2Dvp8f_8cMn5G6CuMfofUpPycFyvvLPQBlbmi7ZF2MBr_nwQ5cc9gfvB0N4H5xffrnqBgdHN0jgb97oPek
linkProvider Scholars Portal
openUrl ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Tumor+microenvironment+governs+the+prognostic+landscape+of+immunotherapy+for+head+and+neck+squamous+cell+carcinoma%3A+A+computational+model-guided+analysis&rft.jtitle=PLoS+computational+biology&rft.au=Bhattacharya%2C+Priyan&rft.au=Linnenbach%2C+Alban&rft.au=South%2C+Andrew+P&rft.au=Martinez-Outschoorn%2C+Ubaldo&rft.date=2025-06-03&rft.issn=1553-7358&rft.eissn=1553-7358&rft.volume=21&rft.issue=6&rft.spage=e1013127&rft_id=info:doi/10.1371%2Fjournal.pcbi.1013127&rft.externalDBID=NO_FULL_TEXT
thumbnail_l http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1553-7358&client=summon
thumbnail_m http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1553-7358&client=summon
thumbnail_s http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1553-7358&client=summon