Antimetabolite pemetrexed primes a favorable tumor microenvironment for immune checkpoint blockade therapy

BackgroundThe immune checkpoint blockade (ICB) targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) has been proved beneficial for numerous types of cancers, including non-small-cell lung cancer (NSCLC). However, a significant number of patients with NSCLC still fail to respond to ICB due...

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Published inJournal for immunotherapy of cancer Vol. 8; no. 2; p. e001392
Main Authors Lu, Chia-Sing, Lin, Ching-Wen, Chang, Ya-Hsuan, Chen, Hsuan-Yu, Chung, Wei-Chia, Lai, Wei-Yun, Ho, Chao-Chi, Wang, Tong-Hong, Chen, Chi-Yuan, Yeh, Chen-Lin, Wu, Sean, Wang, Shu-Ping, Yang, Pan-Chyr
Format Journal Article
LanguageEnglish
Published England BMJ Publishing Group Ltd 01.11.2020
BMJ Publishing Group LTD
BMJ Publishing Group
SeriesOriginal research
Subjects
Antibodies
Basic Tumor Immunology
Blood & organ donations
Cancer
Cancer therapies
Chemotherapy
Cold
combination
costimulatory and inhibitory t-cell receptors
Cytokines
drug therapy
Immunotherapy
Kinases
Lung cancer
Lymphocytes
Monoclonal antibodies
Reactive oxygen species
tumor escape
tumor microenvironment
Tumors
costimulatory and inhibitory t-cell receptors
drug therapy
tumor microenvironment
tumor escape
immunotherapy
combination
Online AccessGet full text
ISSN2051-1426
2051-1426
DOI10.1136/jitc-2020-001392

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Abstract BackgroundThe immune checkpoint blockade (ICB) targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) has been proved beneficial for numerous types of cancers, including non-small-cell lung cancer (NSCLC). However, a significant number of patients with NSCLC still fail to respond to ICB due to unfavorable tumor microenvironment. To improve the efficacy, the immune-chemotherapy combination with pemetrexed, cis/carboplatin and pembrolizumab (anti-PD-1) has been recently approved as first-line treatment in advanced NSCLCs. While chemotherapeutic agents exert beneficial effects, the underlying antitumor mechanism(s) remains unclear.MethodsPemetrexed, cisplatin and other chemotherapeutic agents were tested for the potential to induce PD-L1 expression in NSCLC cells by immunoblotting and flow cytometry. The ability to prime the tumor immune microenvironment was then determined by NSCLC/T cell coculture systems and syngeneic mouse models. Subpopulations of NSCLC cells responding differently to pemetrexed were selected and subjected to RNA-sequencing analysis. The key signaling pathways were identified and validated in vitro and in vivo.ResultsPemetrexed induced the transcriptional activation of PD-L1 (encoded by CD274) by inactivating thymidylate synthase (TS) in NSCLC cells and, in turn, activating T-lymphocytes when combined with the anti-PD-1/PD-L1 therapy. Nuclear factor κB (NF-κB) signaling was activated by intracellular reactive oxygen species (ROSs) that were elevated by pemetrexed-mediated TS inactivation. The TS−ROS−NF-κB regulatory axis actively involves in pemetrexed-induced PD-L1 upregulation, whereas when pemetrexed fails to induce PD-L1 expression in NSCLC cells, NF-κB signaling is unregulated. In syngeneic mouse models, the combinatory treatment of pemetrexed with anti-PD-L1 antibody created a more favorable tumor microenvironment for the inhibition of tumor growth.ConclusionsOur findings reveal novel mechanisms showing that pemetrexed upregulates PD-L1 expression and primes a favorable microenvironment for ICB, which provides a mechanistic basis for the combinatory chemoimmunotherapy in NSCLC treatment.
AbstractList The immune checkpoint blockade (ICB) targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) has been proved beneficial for numerous types of cancers, including non-small-cell lung cancer (NSCLC). However, a significant number of patients with NSCLC still fail to respond to ICB due to unfavorable tumor microenvironment. To improve the efficacy, the immune-chemotherapy combination with pemetrexed, cis/carboplatin and pembrolizumab (anti-PD-1) has been recently approved as first-line treatment in advanced NSCLCs. While chemotherapeutic agents exert beneficial effects, the underlying antitumor mechanism(s) remains unclear. Pemetrexed, cisplatin and other chemotherapeutic agents were tested for the potential to induce PD-L1 expression in NSCLC cells by immunoblotting and flow cytometry. The ability to prime the tumor immune microenvironment was then determined by NSCLC/T cell coculture systems and syngeneic mouse models. Subpopulations of NSCLC cells responding differently to pemetrexed were selected and subjected to RNA-sequencing analysis. The key signaling pathways were identified and validated in vitro and in vivo. Pemetrexed induced the transcriptional activation of (encoded by ) by inactivating thymidylate synthase (TS) in NSCLC cells and, in turn, activating T-lymphocytes when combined with the anti-PD-1/PD-L1 therapy. Nuclear factor κB (NF-κB) signaling was activated by intracellular reactive oxygen species (ROSs) that were elevated by pemetrexed-mediated TS inactivation. The TS-ROS-NF-κB regulatory axis actively involves in pemetrexed-induced PD-L1 upregulation, whereas when pemetrexed fails to induce PD-L1 expression in NSCLC cells, NF-κB signaling is unregulated. In syngeneic mouse models, the combinatory treatment of pemetrexed with anti-PD-L1 antibody created a more favorable tumor microenvironment for the inhibition of tumor growth. Our findings reveal novel mechanisms showing that pemetrexed upregulates PD-L1 expression and primes a favorable microenvironment for ICB, which provides a mechanistic basis for the combinatory chemoimmunotherapy in NSCLC treatment.
BackgroundThe immune checkpoint blockade (ICB) targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) has been proved beneficial for numerous types of cancers, including non-small-cell lung cancer (NSCLC). However, a significant number of patients with NSCLC still fail to respond to ICB due to unfavorable tumor microenvironment. To improve the efficacy, the immune-chemotherapy combination with pemetrexed, cis/carboplatin and pembrolizumab (anti-PD-1) has been recently approved as first-line treatment in advanced NSCLCs. While chemotherapeutic agents exert beneficial effects, the underlying antitumor mechanism(s) remains unclear.MethodsPemetrexed, cisplatin and other chemotherapeutic agents were tested for the potential to induce PD-L1 expression in NSCLC cells by immunoblotting and flow cytometry. The ability to prime the tumor immune microenvironment was then determined by NSCLC/T cell coculture systems and syngeneic mouse models. Subpopulations of NSCLC cells responding differently to pemetrexed were selected and subjected to RNA-sequencing analysis. The key signaling pathways were identified and validated in vitro and in vivo.ResultsPemetrexed induced the transcriptional activation of PD-L1 (encoded by CD274) by inactivating thymidylate synthase (TS) in NSCLC cells and, in turn, activating T-lymphocytes when combined with the anti-PD-1/PD-L1 therapy. Nuclear factor κB (NF-κB) signaling was activated by intracellular reactive oxygen species (ROSs) that were elevated by pemetrexed-mediated TS inactivation. The TS−ROS−NF-κB regulatory axis actively involves in pemetrexed-induced PD-L1 upregulation, whereas when pemetrexed fails to induce PD-L1 expression in NSCLC cells, NF-κB signaling is unregulated. In syngeneic mouse models, the combinatory treatment of pemetrexed with anti-PD-L1 antibody created a more favorable tumor microenvironment for the inhibition of tumor growth.ConclusionsOur findings reveal novel mechanisms showing that pemetrexed upregulates PD-L1 expression and primes a favorable microenvironment for ICB, which provides a mechanistic basis for the combinatory chemoimmunotherapy in NSCLC treatment.
The immune checkpoint blockade (ICB) targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) has been proved beneficial for numerous types of cancers, including non-small-cell lung cancer (NSCLC). However, a significant number of patients with NSCLC still fail to respond to ICB due to unfavorable tumor microenvironment. To improve the efficacy, the immune-chemotherapy combination with pemetrexed, cis/carboplatin and pembrolizumab (anti-PD-1) has been recently approved as first-line treatment in advanced NSCLCs. While chemotherapeutic agents exert beneficial effects, the underlying antitumor mechanism(s) remains unclear.BACKGROUNDThe immune checkpoint blockade (ICB) targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) has been proved beneficial for numerous types of cancers, including non-small-cell lung cancer (NSCLC). However, a significant number of patients with NSCLC still fail to respond to ICB due to unfavorable tumor microenvironment. To improve the efficacy, the immune-chemotherapy combination with pemetrexed, cis/carboplatin and pembrolizumab (anti-PD-1) has been recently approved as first-line treatment in advanced NSCLCs. While chemotherapeutic agents exert beneficial effects, the underlying antitumor mechanism(s) remains unclear.Pemetrexed, cisplatin and other chemotherapeutic agents were tested for the potential to induce PD-L1 expression in NSCLC cells by immunoblotting and flow cytometry. The ability to prime the tumor immune microenvironment was then determined by NSCLC/T cell coculture systems and syngeneic mouse models. Subpopulations of NSCLC cells responding differently to pemetrexed were selected and subjected to RNA-sequencing analysis. The key signaling pathways were identified and validated in vitro and in vivo.METHODSPemetrexed, cisplatin and other chemotherapeutic agents were tested for the potential to induce PD-L1 expression in NSCLC cells by immunoblotting and flow cytometry. The ability to prime the tumor immune microenvironment was then determined by NSCLC/T cell coculture systems and syngeneic mouse models. Subpopulations of NSCLC cells responding differently to pemetrexed were selected and subjected to RNA-sequencing analysis. The key signaling pathways were identified and validated in vitro and in vivo.Pemetrexed induced the transcriptional activation of PD-L1 (encoded by CD274) by inactivating thymidylate synthase (TS) in NSCLC cells and, in turn, activating T-lymphocytes when combined with the anti-PD-1/PD-L1 therapy. Nuclear factor κB (NF-κB) signaling was activated by intracellular reactive oxygen species (ROSs) that were elevated by pemetrexed-mediated TS inactivation. The TS-ROS-NF-κB regulatory axis actively involves in pemetrexed-induced PD-L1 upregulation, whereas when pemetrexed fails to induce PD-L1 expression in NSCLC cells, NF-κB signaling is unregulated. In syngeneic mouse models, the combinatory treatment of pemetrexed with anti-PD-L1 antibody created a more favorable tumor microenvironment for the inhibition of tumor growth.RESULTSPemetrexed induced the transcriptional activation of PD-L1 (encoded by CD274) by inactivating thymidylate synthase (TS) in NSCLC cells and, in turn, activating T-lymphocytes when combined with the anti-PD-1/PD-L1 therapy. Nuclear factor κB (NF-κB) signaling was activated by intracellular reactive oxygen species (ROSs) that were elevated by pemetrexed-mediated TS inactivation. The TS-ROS-NF-κB regulatory axis actively involves in pemetrexed-induced PD-L1 upregulation, whereas when pemetrexed fails to induce PD-L1 expression in NSCLC cells, NF-κB signaling is unregulated. In syngeneic mouse models, the combinatory treatment of pemetrexed with anti-PD-L1 antibody created a more favorable tumor microenvironment for the inhibition of tumor growth.Our findings reveal novel mechanisms showing that pemetrexed upregulates PD-L1 expression and primes a favorable microenvironment for ICB, which provides a mechanistic basis for the combinatory chemoimmunotherapy in NSCLC treatment.CONCLUSIONSOur findings reveal novel mechanisms showing that pemetrexed upregulates PD-L1 expression and primes a favorable microenvironment for ICB, which provides a mechanistic basis for the combinatory chemoimmunotherapy in NSCLC treatment.
Background The immune checkpoint blockade (ICB) targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) has been proved beneficial for numerous types of cancers, including non-small-cell lung cancer (NSCLC). However, a significant number of patients with NSCLC still fail to respond to ICB due to unfavorable tumor microenvironment. To improve the efficacy, the immune-chemotherapy combination with pemetrexed, cis/carboplatin and pembrolizumab (anti-PD-1) has been recently approved as first-line treatment in advanced NSCLCs. While chemotherapeutic agents exert beneficial effects, the underlying antitumor mechanism(s) remains unclear.Methods Pemetrexed, cisplatin and other chemotherapeutic agents were tested for the potential to induce PD-L1 expression in NSCLC cells by immunoblotting and flow cytometry. The ability to prime the tumor immune microenvironment was then determined by NSCLC/T cell coculture systems and syngeneic mouse models. Subpopulations of NSCLC cells responding differently to pemetrexed were selected and subjected to RNA-sequencing analysis. The key signaling pathways were identified and validated in vitro and in vivo.Results Pemetrexed induced the transcriptional activation of PD-L1 (encoded by CD274) by inactivating thymidylate synthase (TS) in NSCLC cells and, in turn, activating T-lymphocytes when combined with the anti-PD-1/PD-L1 therapy. Nuclear factor κB (NF-κB) signaling was activated by intracellular reactive oxygen species (ROSs) that were elevated by pemetrexed-mediated TS inactivation. The TS−ROS−NF-κB regulatory axis actively involves in pemetrexed-induced PD-L1 upregulation, whereas when pemetrexed fails to induce PD-L1 expression in NSCLC cells, NF-κB signaling is unregulated. In syngeneic mouse models, the combinatory treatment of pemetrexed with anti-PD-L1 antibody created a more favorable tumor microenvironment for the inhibition of tumor growth.Conclusions Our findings reveal novel mechanisms showing that pemetrexed upregulates PD-L1 expression and primes a favorable microenvironment for ICB, which provides a mechanistic basis for the combinatory chemoimmunotherapy in NSCLC treatment.
Author Chen, Chi-Yuan
Wang, Tong-Hong
Lin, Ching-Wen
Wang, Shu-Ping
Lu, Chia-Sing
Yeh, Chen-Lin
Wu, Sean
Yang, Pan-Chyr
Chen, Hsuan-Yu
Chang, Ya-Hsuan
Lai, Wei-Yun
Chung, Wei-Chia
Ho, Chao-Chi
AuthorAffiliation 1 Department of Internal Medicine, National Taiwan University Hospital , National Taiwan University College of Medicine , Taipei , Taiwan
2 Institute of Biomedical Sciences , Academia Sinica , Taipei , Taiwan
4 Tissue Bank, Chang Gung Memorial Hospital; Graduate Institute of Health Industry Technology and Research Center for Industry of Human Ecology, College of Human Ecology , Chang Gung University of Science and Technology , Taoyuan , Taiwan
3 Institute of Statistical Science , Academia Sinica , Taipei , Taiwan
5 Institute of Biomedical Sciences and Genomics Research Center , Academia Sinica , Taipei , Taiwan
AuthorAffiliation_xml – name: 1 Department of Internal Medicine, National Taiwan University Hospital , National Taiwan University College of Medicine , Taipei , Taiwan
– name: 5 Institute of Biomedical Sciences and Genomics Research Center , Academia Sinica , Taipei , Taiwan
– name: 3 Institute of Statistical Science , Academia Sinica , Taipei , Taiwan
– name: 2 Institute of Biomedical Sciences , Academia Sinica , Taipei , Taiwan
– name: 4 Tissue Bank, Chang Gung Memorial Hospital; Graduate Institute of Health Industry Technology and Research Center for Industry of Human Ecology, College of Human Ecology , Chang Gung University of Science and Technology , Taoyuan , Taiwan
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  organization: Institute of Biomedical Sciences and Genomics Research Center, Academia Sinica, Taipei, Taiwan
BackLink https://www.ncbi.nlm.nih.gov/pubmed/33243934$$D View this record in MEDLINE/PubMed
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Cites_doi 10.1016/S0140-6736(15)01281-7
10.1158/0008-5472.CAN-07-1179
10.1038/nri3423
10.1038/cdd.2013.67
10.1164/rccm.201207-1180OC
10.1056/NEJMoa1606774
10.1007/s00262-012-1388-0
10.1158/1078-0432.CCR-19-0433
10.1158/0008-5472.CAN-14-3098
10.1634/theoncologist.2018-0084
10.1634/theoncologist.6-4-363
10.1016/j.cyto.2017.05.024
10.1016/S1470-2045(16)30498-3
10.21037/tlcr.2019.10.14
10.1038/s41571-019-0173-9
10.1111/j.1349-7006.2009.01358.x
10.1056/NEJMoa1501824
10.1016/j.trecan.2017.09.006
10.1016/j.canlet.2011.06.006
10.1038/nature04870
10.1016/S0140-6736(16)00587-0
10.1038/nri2326
10.1124/mol.115.099614
10.1007/s00262-004-0593-x
10.1016/j.jtho.2018.08.262
10.1038/nrd1279
10.1101/gad.7.11.2064
10.1038/s41467-020-15364-z
10.1007/s12094-015-1359-y
10.1038/sj.onc.1202657
10.1111/j.1365-2567.2010.03255.x
10.1089/ars.2014.5851
10.1038/nrc1074
10.1038/ni.2035
10.3389/fphar.2017.00561
10.1038/s41467-018-07767-w
10.1042/BST20130156
10.1097/JTO.0000000000000500
10.3322/caac.21551
10.1038/nature14011
10.1038/nri.2016.107
10.1016/j.cllc.2015.07.002
10.1165/ajrcmb.17.3.2837
10.1038/sj.onc.1203239
10.1038/nrc1588
10.1056/NEJMoa1801005
10.1634/theoncologist.2015-0507
10.1016/j.celrep.2017.04.031
10.1016/j.celrep.2019.01.048
10.3389/fimmu.2018.01739
10.1158/1078-0432.CCR-04-0428
10.1158/1078-0432.CCR-14-1213
10.1634/theoncologist.2017-0078
10.1038/s12276-018-0191-1
10.1038/nri2545
10.1073/pnas.90.16.7734
10.1093/annonc/mdy551
10.1038/cr.2010.178
10.3389/fimmu.2018.00288
10.1038/s12276-018-0116-z
10.1158/0008-5472.1089.65.3
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Issue 2
Keywords costimulatory and inhibitory t-cell receptors
drug therapy
tumor microenvironment
tumor escape
immunotherapy
combination
Language English
License This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/.
Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.
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PublicationSeriesTitle Original research
PublicationTitle Journal for immunotherapy of cancer
PublicationTitleAbbrev J Immunother Cancer
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References Kaltschmidt, Kaltschmidt, Hehner (R55) 1999; 18
Nakanishi, Toi (R41) 2005; 5
Bracci, Schiavoni, Sistigu (R14) 2014; 21
Camidge, Doebele, Kerr (R3) 2019; 16
Zou, Chen (R29) 2008; 8
Wherry (R30) 2011; 12
Karin, Yamamoto, Wang (R36) 2004; 3
Suzman, Agrawal, Ning (R6) 2019; 24
Pahl (R37) 1999; 18
Beg, Baldwin (R35) 1993; 7
Herbst, Soria, Kowanetz (R7) 2014; 515
Chen, Emens (R49) 2013; 62
Nathan, Cunningham-Bussel (R42) 2013; 13
Peng, Hamanishi, Matsumura (R59) 2015; 75
Alsaab, Sau, Alzhrani (R47) 2017; 8
Garon, Rizvi, Hui (R10) 2015; 372
Fehrenbacher, Spira, Ballinger (R12) 2016; 387
Pribluda, de la Cruz, Jackson (R32) 2015; 21
Liang, Lu, Chen (R54) 2019; 8
Green, Ferguson, Zitvogel (R24) 2009; 9
Yan, Kumar, Finnes (R16) 2018; 9
Hirano, Kaneko, Tamura (R8) 2005; 65
Ozasa, Oguri, Uemura (R52) 2010; 101
Shimizu, Nakagawa, Takahashi (R53) 2016; 18
Herbst, Baas, Kim (R9) 2016; 387
Hong, Lee, Kim (R58) 2007; 67
Siegel, Miller, Jemal (R1) 2019; 69
Stinchcombe, Borghaei, Barker (R18) 2016; 17
Chu, Yang, Yang (R23) 1997; 17
Schaer, Geeganage, Amaladas (R26) 2019; 25
Longley, Harkin, Johnston (R39) 2003; 3
Showalter, Limaye, Oyer (R48) 2017; 97
Langer, Gadgeel, Borghaei (R19) 2016; 17
Konishi, Yamazaki, Azuma (R11) 2004; 10
Reck, Rodríguez-Abreu, Robinson (R27) 2016; 375
Morgan, Liu, Liu (R40) 2011; 21
Schwarz, Salgame, Bloom (R28) 1993; 90
Blank, Gajewski, Mackensen (R46) 2005; 54
Galluzzi, Buqué, Kepp (R25) 2017; 17
Yeh, Wu, Chang (R22) 2012; 186
Ozer, Barbour, Clinton (R43) 2015; 88
Pai-Scherf, Blumenthal, Li (R5) 2017; 22
Gandhi, Rodríguez-Abreu, Gadgeel (R20) 2018; 378
Heinhuis, Ros, Kok (R15) 2019; 30
Ledoux, Perkins (R56) 2014; 42
Kazandjian, Suzman, Blumenthal (R4) 2016; 21
Jia, Wu, Wang (R34) 2018; 9
Zhang, Ochi, Takigawa (R51) 2011; 309
Cao, Kaufman (R50) 2014; 21
Hanauske, Chen, Paoletti (R17) 2001; 6
Seth, Li, Ho (R33) 2019; 26
Darvin, Toor, Sasidharan Nair, Nair (R2) 2018; 50
Qin, Wang, Ye (R45) 2020; 11
Garcia-Diaz, Shin, Moreno (R38) 2017; 19
Chen, Fang, Zhan (R44) 2015; 10
Karin (R57) 2006; 441
van der Woude, Gorris, Halilovic (R13) 2017; 3
Yi, Cox, Zajac (R31) 2010; 129
Papadimitrakopoulou, Cobo, Bordoni (R21) 2018; 13
Siegel, Miller, Jemal 2019; 69
Morgan, Liu, Liu 2011; 21
Chen, Emens 2013; 62
Longley, Harkin, Johnston 2003; 3
Nathan, Cunningham-Bussel 2013; 13
Chu, Yang, Yang 1997; 17
Bracci, Schiavoni, Sistigu 2014; 21
Schwarz, Salgame, Bloom 1993; 90
Garcia-Diaz, Shin, Moreno 2017; 19
Cao, Kaufman 2014; 21
Yeh, Wu, Chang 2012; 186
Garon, Rizvi, Hui 2015; 372
Suzman, Agrawal, Ning 2019; 24
Heinhuis, Ros, Kok 2019; 30
Showalter, Limaye, Oyer 2017; 97
Peng, Hamanishi, Matsumura 2015; 75
Beg, Baldwin 1993; 7
Hong, Lee, Kim 2007; 67
Reck, Rodríguez-Abreu, Robinson 2016; 375
Seth, Li, Ho 2019; 26
Green, Ferguson, Zitvogel 2009; 9
Yi, Cox, Zajac 2010; 129
Darvin, Toor, Sasidharan Nair, Nair 2018; 50
Camidge, Doebele, Kerr 2019; 16
Karin 2006; 441
Karin, Yamamoto, Wang 2004; 3
Kazandjian, Suzman, Blumenthal 2016; 21
Hanauske, Chen, Paoletti 2001; 6
Chen, Fang, Zhan 2015; 10
Wherry 2011; 12
Konishi, Yamazaki, Azuma 2004; 10
Zou, Chen 2008; 8
Yan, Kumar, Finnes 2018; 9
Ozer, Barbour, Clinton 2015; 88
Herbst, Soria, Kowanetz 2014; 515
Pahl 1999; 18
Alsaab, Sau, Alzhrani 2017; 8
van der Woude, Gorris, Halilovic 2017; 3
Ledoux, Perkins 2014; 42
Galluzzi, Buqué, Kepp 2017; 17
Pribluda, de la Cruz, Jackson 2015; 21
Langer, Gadgeel, Borghaei 2016; 17
Stinchcombe, Borghaei, Barker 2016; 17
Ozasa, Oguri, Uemura 2010; 101
Pai-Scherf, Blumenthal, Li 2017; 22
Nakanishi, Toi 2005; 5
Gandhi, Rodríguez-Abreu, Gadgeel 2018; 378
Jia, Wu, Wang 2018; 9
Hirano, Kaneko, Tamura 2005; 65
Schaer, Geeganage, Amaladas 2019; 25
Shimizu, Nakagawa, Takahashi 2016; 18
Herbst, Baas, Kim 2016; 387
Zhang, Ochi, Takigawa 2011; 309
Qin, Wang, Ye 2020; 11
Blank, Gajewski, Mackensen 2005; 54
Papadimitrakopoulou, Cobo, Bordoni 2018; 13
Kaltschmidt, Kaltschmidt, Hehner 1999; 18
Liang, Lu, Chen 2019; 8
Fehrenbacher, Spira, Ballinger 2016; 387
2025032605451556000_8.2.e001392.1
2025032605451556000_8.2.e001392.41
2025032605451556000_8.2.e001392.40
van der Woude (2025032605451556000_8.2.e001392.13) 2017; 3
2025032605451556000_8.2.e001392.36
2025032605451556000_8.2.e001392.35
2025032605451556000_8.2.e001392.37
2025032605451556000_8.2.e001392.32
2025032605451556000_8.2.e001392.31
2025032605451556000_8.2.e001392.34
2025032605451556000_8.2.e001392.5
2025032605451556000_8.2.e001392.4
2025032605451556000_8.2.e001392.2
2025032605451556000_8.2.e001392.9
2025032605451556000_8.2.e001392.39
2025032605451556000_8.2.e001392.7
Shimizu (2025032605451556000_8.2.e001392.53) 2016; 18
2025032605451556000_8.2.e001392.6
Liang (2025032605451556000_8.2.e001392.54) 2019; 8
2025032605451556000_8.2.e001392.30
2025032605451556000_8.2.e001392.25
2025032605451556000_8.2.e001392.24
Garcia-Diaz (2025032605451556000_8.2.e001392.38) 2017; 19
Showalter (2025032605451556000_8.2.e001392.48) 2017; 97
2025032605451556000_8.2.e001392.27
2025032605451556000_8.2.e001392.26
2025032605451556000_8.2.e001392.20
2025032605451556000_8.2.e001392.23
2025032605451556000_8.2.e001392.22
2025032605451556000_8.2.e001392.29
2025032605451556000_8.2.e001392.28
Hirano (2025032605451556000_8.2.e001392.8) 2005; 65
2025032605451556000_8.2.e001392.14
2025032605451556000_8.2.e001392.58
2025032605451556000_8.2.e001392.57
2025032605451556000_8.2.e001392.16
2025032605451556000_8.2.e001392.59
2025032605451556000_8.2.e001392.10
Seth (2025032605451556000_8.2.e001392.33) 2019; 26
2025032605451556000_8.2.e001392.12
2025032605451556000_8.2.e001392.56
2025032605451556000_8.2.e001392.11
2025032605451556000_8.2.e001392.55
Papadimitrakopoulou (2025032605451556000_8.2.e001392.21) 2018; 13
2025032605451556000_8.2.e001392.18
2025032605451556000_8.2.e001392.17
2025032605451556000_8.2.e001392.19
Qin (2025032605451556000_8.2.e001392.45) 2020; 11
2025032605451556000_8.2.e001392.50
2025032605451556000_8.2.e001392.52
2025032605451556000_8.2.e001392.51
Camidge (2025032605451556000_8.2.e001392.3) 2019; 16
2025032605451556000_8.2.e001392.47
2025032605451556000_8.2.e001392.46
2025032605451556000_8.2.e001392.49
2025032605451556000_8.2.e001392.43
2025032605451556000_8.2.e001392.42
2025032605451556000_8.2.e001392.44
Heinhuis (2025032605451556000_8.2.e001392.15) 2019; 30
References_xml – volume: 387
  start-page: 1540
  year: 2016
  ident: R9
  article-title: Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial
  publication-title: Lancet
  doi: 10.1016/S0140-6736(15)01281-7
– volume: 67
  start-page: 9577
  year: 2007
  ident: R58
  article-title: Smad7 sensitizes tumor necrosis factor induced apoptosis through the inhibition of antiapoptotic gene expression by suppressing activation of the nuclear factor-kappaB pathway
  publication-title: Cancer Res
  doi: 10.1158/0008-5472.CAN-07-1179
– volume: 13
  start-page: 349
  year: 2013
  ident: R42
  article-title: Beyond oxidative stress: an Immunologist's guide to reactive oxygen species
  publication-title: Nat Rev Immunol
  doi: 10.1038/nri3423
– volume: 21
  start-page: 15
  year: 2014
  ident: R14
  article-title: Immune-Based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer
  publication-title: Cell Death Differ
  doi: 10.1038/cdd.2013.67
– volume: 186
  start-page: 1180
  year: 2012
  ident: R22
  article-title: Trifluoperazine, an antipsychotic agent, inhibits cancer stem cell growth and overcomes drug resistance of lung cancer
  publication-title: Am J Respir Crit Care Med
  doi: 10.1164/rccm.201207-1180OC
– volume: 375
  start-page: 1823
  year: 2016
  ident: R27
  article-title: Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer
  publication-title: N Engl J Med
  doi: 10.1056/NEJMoa1606774
– volume: 62
  start-page: 203
  year: 2013
  ident: R49
  article-title: Chemoimmunotherapy: reengineering tumor immunity
  publication-title: Cancer Immunol Immunother
  doi: 10.1007/s00262-012-1388-0
– volume: 25
  start-page: 7175
  year: 2019
  ident: R26
  article-title: The folate pathway inhibitor pemetrexed pleiotropically enhances effects of cancer immunotherapy
  publication-title: Clin Cancer Res
  doi: 10.1158/1078-0432.CCR-19-0433
– volume: 75
  start-page: 5034
  year: 2015
  ident: R59
  article-title: Chemotherapy induces programmed cell Death-Ligand 1 overexpression via the nuclear factor-κB to foster an immunosuppressive tumor microenvironment in ovarian cancer
  publication-title: Cancer Res
  doi: 10.1158/0008-5472.CAN-14-3098
– volume: 24
  start-page: 563
  year: 2019
  ident: R6
  article-title: Fda approval summary: Atezolizumab or pembrolizumab for the treatment of patients with advanced urothelial carcinoma ineligible for cisplatin-containing chemotherapy
  publication-title: Oncologist
  doi: 10.1634/theoncologist.2018-0084
– volume: 6
  start-page: 363
  year: 2001
  ident: R17
  article-title: Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors
  publication-title: Oncologist
  doi: 10.1634/theoncologist.6-4-363
– volume: 97
  start-page: 123
  year: 2017
  ident: R48
  article-title: Cytokines in immunogenic cell death: applications for cancer immunotherapy
  publication-title: Cytokine
  doi: 10.1016/j.cyto.2017.05.024
– volume: 17
  start-page: 1497
  year: 2016
  ident: R19
  article-title: Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study
  publication-title: Lancet Oncol
  doi: 10.1016/S1470-2045(16)30498-3
– volume: 8
  start-page: 1107
  year: 2019
  ident: R54
  article-title: Mechanisms of resistance to pemetrexed in non-small cell lung cancer
  publication-title: Transl Lung Cancer Res
  doi: 10.21037/tlcr.2019.10.14
– volume: 16
  start-page: 341
  year: 2019
  ident: R3
  article-title: Comparing and contrasting predictive biomarkers for immunotherapy and targeted therapy of NSCLC
  publication-title: Nat Rev Clin Oncol
  doi: 10.1038/s41571-019-0173-9
– volume: 101
  start-page: 161
  year: 2010
  ident: R52
  article-title: Significance of thymidylate synthase for resistance to pemetrexed in lung cancer
  publication-title: Cancer Sci
  doi: 10.1111/j.1349-7006.2009.01358.x
– volume: 372
  start-page: 2018
  year: 2015
  ident: R10
  article-title: Pembrolizumab for the treatment of non-small-cell lung cancer
  publication-title: N Engl J Med
  doi: 10.1056/NEJMoa1501824
– volume: 3
  start-page: 797
  year: 2017
  ident: R13
  article-title: Migrating into the tumor: a roadmap for T cells
  publication-title: Trends Cancer
  doi: 10.1016/j.trecan.2017.09.006
– volume: 309
  start-page: 228
  year: 2011
  ident: R51
  article-title: Establishment of pemetrexed-resistant non-small cell lung cancer cell lines
  publication-title: Cancer Lett
  doi: 10.1016/j.canlet.2011.06.006
– volume: 441
  start-page: 431
  year: 2006
  ident: R57
  article-title: Nuclear factor-kappaB in cancer development and progression
  publication-title: Nature
  doi: 10.1038/nature04870
– volume: 387
  start-page: 1837
  year: 2016
  ident: R12
  article-title: Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (poplar): a multicentre, open-label, phase 2 randomised controlled trial
  publication-title: Lancet
  doi: 10.1016/S0140-6736(16)00587-0
– volume: 8
  start-page: 467
  year: 2008
  ident: R29
  article-title: Inhibitory B7-family molecules in the tumour microenvironment
  publication-title: Nat Rev Immunol
  doi: 10.1038/nri2326
– volume: 88
  start-page: 970
  year: 2015
  ident: R43
  article-title: Oxidative stress and response to thymidylate Synthase-Targeted antimetabolites
  publication-title: Mol Pharmacol
  doi: 10.1124/mol.115.099614
– volume: 54
  start-page: 307
  year: 2005
  ident: R46
  article-title: Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy
  publication-title: Cancer Immunol Immunother
  doi: 10.1007/s00262-004-0593-x
– volume: 13
  start-page: S332
  year: 2018
  ident: R21
  article-title: OA05.07 IMpower132: pfs and safety results with 1L Atezolizumab + Carboplatin/Cisplatin + pemetrexed in stage IV non-squamous NSCLC
  publication-title: J Thorac Oncol
  doi: 10.1016/j.jtho.2018.08.262
– volume: 65
  start-page: 1089
  year: 2005
  ident: R8
  article-title: Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity
  publication-title: Cancer Res
– volume: 3
  start-page: 17
  year: 2004
  ident: R36
  article-title: The IKK NF-kappa B system: a treasure trove for drug development
  publication-title: Nat Rev Drug Discov
  doi: 10.1038/nrd1279
– volume: 7
  start-page: 2064
  year: 1993
  ident: R35
  article-title: The I kappa B proteins: multifunctional regulators of rel/NF-kappa B transcription factors
  publication-title: Genes Dev
  doi: 10.1101/gad.7.11.2064
– volume: 11
  year: 2020
  ident: R45
  article-title: Npm1 upregulates the transcription of PD-L1 and suppresses T cell activity in triple-negative breast cancer
  publication-title: Nat Commun
  doi: 10.1038/s41467-020-15364-z
– volume: 18
  start-page: 107
  year: 2016
  ident: R53
  article-title: Thymidylate synthase gene amplification predicts pemetrexed resistance in patients with advanced non-small cell lung cancer
  publication-title: Clin Transl Oncol
  doi: 10.1007/s12094-015-1359-y
– volume: 18
  start-page: 3213
  year: 1999
  ident: R55
  article-title: Repression of NF-kappaB impairs HeLa cell proliferation by functional interference with cell cycle checkpoint regulators
  publication-title: Oncogene
  doi: 10.1038/sj.onc.1202657
– volume: 129
  start-page: 474
  year: 2010
  ident: R31
  article-title: T-Cell exhaustion: characteristics, causes and conversion
  publication-title: Immunology
  doi: 10.1111/j.1365-2567.2010.03255.x
– volume: 21
  start-page: 396
  year: 2014
  ident: R50
  article-title: Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease
  publication-title: Antioxid Redox Signal
  doi: 10.1089/ars.2014.5851
– volume: 3
  start-page: 330
  year: 2003
  ident: R39
  article-title: 5-Fluorouracil: mechanisms of action and clinical strategies
  publication-title: Nat Rev Cancer
  doi: 10.1038/nrc1074
– volume: 12
  start-page: 492
  year: 2011
  ident: R30
  article-title: T cell exhaustion
  publication-title: Nat Immunol
  doi: 10.1038/ni.2035
– volume: 8
  year: 2017
  ident: R47
  article-title: Pd-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome
  publication-title: Front Pharmacol
  doi: 10.3389/fphar.2017.00561
– volume: 9
  year: 2018
  ident: R34
  article-title: Local mutational diversity drives intratumoral immune heterogeneity in non-small cell lung cancer
  publication-title: Nat Commun
  doi: 10.1038/s41467-018-07767-w
– volume: 42
  start-page: 76
  year: 2014
  ident: R56
  article-title: NF-κB and the cell cycle
  publication-title: Biochem Soc Trans
  doi: 10.1042/BST20130156
– volume: 10
  start-page: 910
  year: 2015
  ident: R44
  article-title: Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-Driven NSCLC: implication for optional immune targeted therapy for NSCLC patients with EGFR mutation
  publication-title: J Thorac Oncol
  doi: 10.1097/JTO.0000000000000500
– volume: 69
  start-page: 7
  year: 2019
  ident: R1
  article-title: Cancer statistics, 2019
  publication-title: CA Cancer J Clin
  doi: 10.3322/caac.21551
– volume: 515
  start-page: 563
  year: 2014
  ident: R7
  article-title: Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients
  publication-title: Nature
  doi: 10.1038/nature14011
– volume: 17
  start-page: 97
  year: 2017
  ident: R25
  article-title: Immunogenic cell death in cancer and infectious disease
  publication-title: Nat Rev Immunol
  doi: 10.1038/nri.2016.107
– volume: 17
  start-page: 1
  year: 2016
  ident: R18
  article-title: Pemetrexed with platinum combination as a backbone for targeted therapy in non-small-cell lung cancer
  publication-title: Clin Lung Cancer
  doi: 10.1016/j.cllc.2015.07.002
– volume: 17
  start-page: 353
  year: 1997
  ident: R23
  article-title: Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line
  publication-title: Am J Respir Cell Mol Biol
  doi: 10.1165/ajrcmb.17.3.2837
– volume: 18
  start-page: 6853
  year: 1999
  ident: R37
  article-title: Activators and target genes of Rel/NF-kappaB transcription factors
  publication-title: Oncogene
  doi: 10.1038/sj.onc.1203239
– volume: 5
  start-page: 297
  year: 2005
  ident: R41
  article-title: Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs
  publication-title: Nat Rev Cancer
  doi: 10.1038/nrc1588
– volume: 378
  start-page: 2078
  year: 2018
  ident: R20
  article-title: Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer
  publication-title: N Engl J Med
  doi: 10.1056/NEJMoa1801005
– volume: 21
  start-page: 634
  year: 2016
  ident: R4
  article-title: Fda approval summary: nivolumab for the treatment of metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy
  publication-title: Oncologist
  doi: 10.1634/theoncologist.2015-0507
– volume: 19
  start-page: 1189
  year: 2017
  ident: R38
  article-title: Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression
  publication-title: Cell Rep
  doi: 10.1016/j.celrep.2017.04.031
– volume: 26
  start-page: 1518
  year: 2019
  ident: R33
  article-title: Pre-Existing functional heterogeneity of tumorigenic compartment as the origin of chemoresistance in pancreatic tumors
  publication-title: Cell Rep
  doi: 10.1016/j.celrep.2019.01.048
– volume: 9
  year: 2018
  ident: R16
  article-title: Combining immune checkpoint inhibitors with conventional cancer therapy
  publication-title: Front Immunol
  doi: 10.3389/fimmu.2018.01739
– volume: 10
  start-page: 5094
  year: 2004
  ident: R11
  article-title: B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression
  publication-title: Clin Cancer Res
  doi: 10.1158/1078-0432.CCR-04-0428
– volume: 21
  start-page: 2916
  year: 2015
  ident: R32
  article-title: Intratumoral heterogeneity: from diversity comes resistance
  publication-title: Clin Cancer Res
  doi: 10.1158/1078-0432.CCR-14-1213
– volume: 22
  start-page: 1392
  year: 2017
  ident: R5
  article-title: Fda approval summary: pembrolizumab for treatment of metastatic non-small cell lung cancer: first-line therapy and beyond
  publication-title: Oncologist
  doi: 10.1634/theoncologist.2017-0078
– volume: 50
  start-page: 1
  year: 2018
  ident: R2
  article-title: Immune checkpoint inhibitors: recent progress and potential biomarkers
  publication-title: Exp Mol Med
  doi: 10.1038/s12276-018-0191-1
– volume: 9
  start-page: 353
  year: 2009
  ident: R24
  article-title: Immunogenic and tolerogenic cell death
  publication-title: Nat Rev Immunol
  doi: 10.1038/nri2545
– volume: 90
  start-page: 7734
  year: 1993
  ident: R28
  article-title: Molecular regulation of human interleukin 2 and T-cell function by interleukin 4
  publication-title: Proc Natl Acad Sci U S A
  doi: 10.1073/pnas.90.16.7734
– volume: 30
  start-page: 219
  year: 2019
  ident: R15
  article-title: Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors
  publication-title: Ann Oncol
  doi: 10.1093/annonc/mdy551
– volume: 21
  start-page: 103
  year: 2011
  ident: R40
  article-title: Crosstalk of reactive oxygen species and NF-κB signaling
  publication-title: Cell Res
  doi: 10.1038/cr.2010.178
– volume: 378
  start-page: 2078
  year: 2018
  article-title: Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer
  publication-title: N Engl J Med
  doi: 10.1056/NEJMoa1801005
– volume: 30
  start-page: 219
  year: 2019
  article-title: Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors
  publication-title: Ann Oncol
  doi: 10.1093/annonc/mdy551
– volume: 7
  start-page: 2064
  year: 1993
  article-title: The I kappa B proteins: multifunctional regulators of rel/NF-kappa B transcription factors
  publication-title: Genes Dev
  doi: 10.1101/gad.7.11.2064
– volume: 18
  start-page: 3213
  year: 1999
  article-title: Repression of NF-kappaB impairs HeLa cell proliferation by functional interference with cell cycle checkpoint regulators
  publication-title: Oncogene
  doi: 10.1038/sj.onc.1202657
– volume: 372
  start-page: 2018
  year: 2015
  article-title: Pembrolizumab for the treatment of non-small-cell lung cancer
  publication-title: N Engl J Med
  doi: 10.1056/NEJMoa1501824
– volume: 10
  start-page: 5094
  year: 2004
  article-title: B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression
  publication-title: Clin Cancer Res
  doi: 10.1158/1078-0432.CCR-04-0428
– volume: 3
  start-page: 17
  year: 2004
  article-title: The IKK NF-kappa B system: a treasure trove for drug development
  publication-title: Nat Rev Drug Discov
  doi: 10.1038/nrd1279
– volume: 18
  start-page: 107
  year: 2016
  article-title: Thymidylate synthase gene amplification predicts pemetrexed resistance in patients with advanced non-small cell lung cancer
  publication-title: Clin Transl Oncol
  doi: 10.1007/s12094-015-1359-y
– volume: 16
  start-page: 341
  year: 2019
  article-title: Comparing and contrasting predictive biomarkers for immunotherapy and targeted therapy of NSCLC
  publication-title: Nat Rev Clin Oncol
  doi: 10.1038/s41571-019-0173-9
– volume: 88
  start-page: 970
  year: 2015
  article-title: Oxidative stress and response to thymidylate Synthase-Targeted antimetabolites
  publication-title: Mol Pharmacol
  doi: 10.1124/mol.115.099614
– volume: 129
  start-page: 474
  year: 2010
  article-title: T-Cell exhaustion: characteristics, causes and conversion
  publication-title: Immunology
  doi: 10.1111/j.1365-2567.2010.03255.x
– volume: 101
  start-page: 161
  year: 2010
  article-title: Significance of thymidylate synthase for resistance to pemetrexed in lung cancer
  publication-title: Cancer Sci
  doi: 10.1111/j.1349-7006.2009.01358.x
– volume: 21
  start-page: 2916
  year: 2015
  article-title: Intratumoral heterogeneity: from diversity comes resistance
  publication-title: Clin Cancer Res
  doi: 10.1158/1078-0432.CCR-14-1213
– volume: 375
  start-page: 1823
  year: 2016
  article-title: Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer
  publication-title: N Engl J Med
  doi: 10.1056/NEJMoa1606774
– volume: 19
  start-page: 1189
  year: 2017
  article-title: Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression
  publication-title: Cell Rep
  doi: 10.1016/j.celrep.2017.04.031
– volume: 8
  year: 2017
  article-title: Pd-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome
  publication-title: Front Pharmacol
  doi: 10.3389/fphar.2017.00561
– volume: 9
  start-page: 353
  year: 2009
  article-title: Immunogenic and tolerogenic cell death
  publication-title: Nat Rev Immunol
  doi: 10.1038/nri2545
– volume: 5
  start-page: 297
  year: 2005
  article-title: Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs
  publication-title: Nat Rev Cancer
  doi: 10.1038/nrc1588
– volume: 75
  start-page: 5034
  year: 2015
  article-title: Chemotherapy induces programmed cell Death-Ligand 1 overexpression via the nuclear factor-κB to foster an immunosuppressive tumor microenvironment in ovarian cancer
  publication-title: Cancer Res
  doi: 10.1158/0008-5472.CAN-14-3098
– volume: 21
  start-page: 634
  year: 2016
  article-title: Fda approval summary: nivolumab for the treatment of metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy
  publication-title: Oncologist
  doi: 10.1634/theoncologist.2015-0507
– volume: 186
  start-page: 1180
  year: 2012
  article-title: Trifluoperazine, an antipsychotic agent, inhibits cancer stem cell growth and overcomes drug resistance of lung cancer
  publication-title: Am J Respir Crit Care Med
  doi: 10.1164/rccm.201207-1180OC
– volume: 25
  start-page: 7175
  year: 2019
  article-title: The folate pathway inhibitor pemetrexed pleiotropically enhances effects of cancer immunotherapy
  publication-title: Clin Cancer Res
  doi: 10.1158/1078-0432.CCR-19-0433
– volume: 50
  start-page: 1
  year: 2018
  article-title: Immune checkpoint inhibitors: recent progress and potential biomarkers
  publication-title: Exp Mol Med
  doi: 10.1038/s12276-018-0191-1
– volume: 24
  start-page: 563
  year: 2019
  article-title: Fda approval summary: Atezolizumab or pembrolizumab for the treatment of patients with advanced urothelial carcinoma ineligible for cisplatin-containing chemotherapy
  publication-title: Oncologist
  doi: 10.1634/theoncologist.2018-0084
– volume: 22
  start-page: 1392
  year: 2017
  article-title: Fda approval summary: pembrolizumab for treatment of metastatic non-small cell lung cancer: first-line therapy and beyond
  publication-title: Oncologist
  doi: 10.1634/theoncologist.2017-0078
– volume: 62
  start-page: 203
  year: 2013
  article-title: Chemoimmunotherapy: reengineering tumor immunity
  publication-title: Cancer Immunol Immunother
  doi: 10.1007/s00262-012-1388-0
– volume: 8
  start-page: 1107
  year: 2019
  article-title: Mechanisms of resistance to pemetrexed in non-small cell lung cancer
  publication-title: Transl Lung Cancer Res
  doi: 10.21037/tlcr.2019.10.14
– volume: 13
  start-page: 349
  year: 2013
  article-title: Beyond oxidative stress: an Immunologist's guide to reactive oxygen species
  publication-title: Nat Rev Immunol
  doi: 10.1038/nri3423
– volume: 12
  start-page: 492
  year: 2011
  article-title: T cell exhaustion
  publication-title: Nat Immunol
  doi: 10.1038/ni.2035
– volume: 8
  start-page: 467
  year: 2008
  article-title: Inhibitory B7-family molecules in the tumour microenvironment
  publication-title: Nat Rev Immunol
  doi: 10.1038/nri2326
– volume: 65
  start-page: 1089
  year: 2005
  article-title: Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity
  publication-title: Cancer Res
– volume: 441
  start-page: 431
  year: 2006
  article-title: Nuclear factor-kappaB in cancer development and progression
  publication-title: Nature
  doi: 10.1038/nature04870
– volume: 90
  start-page: 7734
  year: 1993
  article-title: Molecular regulation of human interleukin 2 and T-cell function by interleukin 4
  publication-title: Proc Natl Acad Sci U S A
  doi: 10.1073/pnas.90.16.7734
– volume: 17
  start-page: 1497
  year: 2016
  article-title: Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study
  publication-title: Lancet Oncol
  doi: 10.1016/S1470-2045(16)30498-3
– volume: 3
  start-page: 797
  year: 2017
  article-title: Migrating into the tumor: a roadmap for T cells
  publication-title: Trends Cancer
  doi: 10.1016/j.trecan.2017.09.006
– volume: 17
  start-page: 97
  year: 2017
  article-title: Immunogenic cell death in cancer and infectious disease
  publication-title: Nat Rev Immunol
  doi: 10.1038/nri.2016.107
– volume: 54
  start-page: 307
  year: 2005
  article-title: Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy
  publication-title: Cancer Immunol Immunother
  doi: 10.1007/s00262-004-0593-x
– volume: 17
  start-page: 353
  year: 1997
  article-title: Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line
  publication-title: Am J Respir Cell Mol Biol
  doi: 10.1165/ajrcmb.17.3.2837
– volume: 515
  start-page: 563
  year: 2014
  article-title: Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients
  publication-title: Nature
  doi: 10.1038/nature14011
– volume: 387
  start-page: 1837
  year: 2016
  article-title: Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (poplar): a multicentre, open-label, phase 2 randomised controlled trial
  publication-title: Lancet
  doi: 10.1016/S0140-6736(16)00587-0
– volume: 21
  start-page: 396
  year: 2014
  article-title: Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease
  publication-title: Antioxid Redox Signal
  doi: 10.1089/ars.2014.5851
– volume: 67
  start-page: 9577
  year: 2007
  article-title: Smad7 sensitizes tumor necrosis factor induced apoptosis through the inhibition of antiapoptotic gene expression by suppressing activation of the nuclear factor-kappaB pathway
  publication-title: Cancer Res
  doi: 10.1158/0008-5472.CAN-07-1179
– volume: 387
  start-page: 1540
  year: 2016
  article-title: Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial
  publication-title: Lancet
  doi: 10.1016/S0140-6736(15)01281-7
– volume: 26
  start-page: 1518
  year: 2019
  article-title: Pre-Existing functional heterogeneity of tumorigenic compartment as the origin of chemoresistance in pancreatic tumors
  publication-title: Cell Rep
  doi: 10.1016/j.celrep.2019.01.048
– volume: 21
  start-page: 103
  year: 2011
  article-title: Crosstalk of reactive oxygen species and NF-κB signaling
  publication-title: Cell Res
  doi: 10.1038/cr.2010.178
– volume: 18
  start-page: 6853
  year: 1999
  article-title: Activators and target genes of Rel/NF-kappaB transcription factors
  publication-title: Oncogene
  doi: 10.1038/sj.onc.1203239
– volume: 3
  start-page: 330
  year: 2003
  article-title: 5-Fluorouracil: mechanisms of action and clinical strategies
  publication-title: Nat Rev Cancer
  doi: 10.1038/nrc1074
– volume: 21
  start-page: 15
  year: 2014
  article-title: Immune-Based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer
  publication-title: Cell Death Differ
  doi: 10.1038/cdd.2013.67
– volume: 9
  year: 2018
  article-title: Combining immune checkpoint inhibitors with conventional cancer therapy
  publication-title: Front Immunol
  doi: 10.3389/fimmu.2018.01739
– volume: 9
  year: 2018
  article-title: Local mutational diversity drives intratumoral immune heterogeneity in non-small cell lung cancer
  publication-title: Nat Commun
  doi: 10.1038/s41467-018-07767-w
– volume: 309
  start-page: 228
  year: 2011
  article-title: Establishment of pemetrexed-resistant non-small cell lung cancer cell lines
  publication-title: Cancer Lett
  doi: 10.1016/j.canlet.2011.06.006
– volume: 6
  start-page: 363
  year: 2001
  article-title: Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors
  publication-title: Oncologist
  doi: 10.1634/theoncologist.6-4-363
– volume: 42
  start-page: 76
  year: 2014
  article-title: NF-κB and the cell cycle
  publication-title: Biochem Soc Trans
  doi: 10.1042/BST20130156
– volume: 17
  start-page: 1
  year: 2016
  article-title: Pemetrexed with platinum combination as a backbone for targeted therapy in non-small-cell lung cancer
  publication-title: Clin Lung Cancer
  doi: 10.1016/j.cllc.2015.07.002
– volume: 11
  year: 2020
  article-title: Npm1 upregulates the transcription of PD-L1 and suppresses T cell activity in triple-negative breast cancer
  publication-title: Nat Commun
  doi: 10.1038/s41467-020-15364-z
– volume: 97
  start-page: 123
  year: 2017
  article-title: Cytokines in immunogenic cell death: applications for cancer immunotherapy
  publication-title: Cytokine
  doi: 10.1016/j.cyto.2017.05.024
– volume: 13
  start-page: S332
  year: 2018
  article-title: OA05.07 IMpower132: pfs and safety results with 1L Atezolizumab + Carboplatin/Cisplatin + pemetrexed in stage IV non-squamous NSCLC
  publication-title: J Thorac Oncol
  doi: 10.1016/j.jtho.2018.08.262
– volume: 10
  start-page: 910
  year: 2015
  article-title: Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-Driven NSCLC: implication for optional immune targeted therapy for NSCLC patients with EGFR mutation
  publication-title: J Thorac Oncol
  doi: 10.1097/JTO.0000000000000500
– volume: 69
  start-page: 7
  year: 2019
  article-title: Cancer statistics, 2019
  publication-title: CA Cancer J Clin
  doi: 10.3322/caac.21551
– ident: 2025032605451556000_8.2.e001392.6
  doi: 10.1634/theoncologist.2018-0084
– ident: 2025032605451556000_8.2.e001392.16
  doi: 10.3389/fimmu.2018.00288
– ident: 2025032605451556000_8.2.e001392.58
  doi: 10.1158/0008-5472.CAN-07-1179
– ident: 2025032605451556000_8.2.e001392.12
  doi: 10.1016/S0140-6736(16)00587-0
– ident: 2025032605451556000_8.2.e001392.26
  doi: 10.1158/1078-0432.CCR-19-0433
– ident: 2025032605451556000_8.2.e001392.57
  doi: 10.1038/nature04870
– ident: 2025032605451556000_8.2.e001392.36
  doi: 10.1038/nrd1279
– ident: 2025032605451556000_8.2.e001392.47
  doi: 10.3389/fphar.2017.00561
– ident: 2025032605451556000_8.2.e001392.1
  doi: 10.3322/caac.21551
– ident: 2025032605451556000_8.2.e001392.40
  doi: 10.1038/cr.2010.178
– ident: 2025032605451556000_8.2.e001392.46
  doi: 10.1007/s00262-004-0593-x
– volume: 3
  start-page: 797
  year: 2017
  ident: 2025032605451556000_8.2.e001392.13
  article-title: Migrating into the tumor: a roadmap for T cells
  publication-title: Trends Cancer
  doi: 10.1016/j.trecan.2017.09.006
– ident: 2025032605451556000_8.2.e001392.23
  doi: 10.1165/ajrcmb.17.3.2837
– volume: 18
  start-page: 107
  year: 2016
  ident: 2025032605451556000_8.2.e001392.53
  article-title: Thymidylate synthase gene amplification predicts pemetrexed resistance in patients with advanced non-small cell lung cancer
  publication-title: Clin Transl Oncol
  doi: 10.1007/s12094-015-1359-y
– ident: 2025032605451556000_8.2.e001392.20
  doi: 10.1056/NEJMoa1801005
– ident: 2025032605451556000_8.2.e001392.27
  doi: 10.1056/NEJMoa1606774
– volume: 26
  start-page: 1518
  year: 2019
  ident: 2025032605451556000_8.2.e001392.33
  article-title: Pre-Existing functional heterogeneity of tumorigenic compartment as the origin of chemoresistance in pancreatic tumors
  publication-title: Cell Rep
  doi: 10.1016/j.celrep.2019.01.048
– ident: 2025032605451556000_8.2.e001392.34
  doi: 10.1038/s41467-018-07767-w
– ident: 2025032605451556000_8.2.e001392.28
  doi: 10.1073/pnas.90.16.7734
– ident: 2025032605451556000_8.2.e001392.29
  doi: 10.1038/nri2326
– volume: 19
  start-page: 1189
  year: 2017
  ident: 2025032605451556000_8.2.e001392.38
  article-title: Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression
  publication-title: Cell Rep
  doi: 10.1016/j.celrep.2017.04.031
– ident: 2025032605451556000_8.2.e001392.39
  doi: 10.1038/nrc1074
– ident: 2025032605451556000_8.2.e001392.50
  doi: 10.1089/ars.2014.5851
– volume: 8
  start-page: 1107
  year: 2019
  ident: 2025032605451556000_8.2.e001392.54
  article-title: Mechanisms of resistance to pemetrexed in non-small cell lung cancer
  publication-title: Transl Lung Cancer Res
  doi: 10.21037/tlcr.2019.10.14
– ident: 2025032605451556000_8.2.e001392.31
  doi: 10.1111/j.1365-2567.2010.03255.x
– ident: 2025032605451556000_8.2.e001392.35
  doi: 10.1101/gad.7.11.2064
– ident: 2025032605451556000_8.2.e001392.19
  doi: 10.1016/S1470-2045(16)30498-3
– ident: 2025032605451556000_8.2.e001392.37
  doi: 10.1038/sj.onc.1203239
– ident: 2025032605451556000_8.2.e001392.41
  doi: 10.1038/nrc1588
– ident: 2025032605451556000_8.2.e001392.4
  doi: 10.1634/theoncologist.2015-0507
– ident: 2025032605451556000_8.2.e001392.44
  doi: 10.1097/JTO.0000000000000500
– ident: 2025032605451556000_8.2.e001392.49
  doi: 10.1007/s00262-012-1388-0
– ident: 2025032605451556000_8.2.e001392.11
  doi: 10.1158/1078-0432.CCR-04-0428
– ident: 2025032605451556000_8.2.e001392.2
  doi: 10.1038/s12276-018-0116-z
– ident: 2025032605451556000_8.2.e001392.7
  doi: 10.1038/nature14011
– ident: 2025032605451556000_8.2.e001392.17
  doi: 10.1634/theoncologist.6-4-363
– volume: 13
  start-page: S332
  year: 2018
  ident: 2025032605451556000_8.2.e001392.21
  article-title: OA05.07 IMpower132: pfs and safety results with 1L Atezolizumab + Carboplatin/Cisplatin + pemetrexed in stage IV non-squamous NSCLC
  publication-title: J Thorac Oncol
  doi: 10.1016/j.jtho.2018.08.262
– ident: 2025032605451556000_8.2.e001392.24
  doi: 10.1038/nri2545
– ident: 2025032605451556000_8.2.e001392.32
  doi: 10.1158/1078-0432.CCR-14-1213
– ident: 2025032605451556000_8.2.e001392.52
  doi: 10.1111/j.1349-7006.2009.01358.x
– ident: 2025032605451556000_8.2.e001392.55
  doi: 10.1038/sj.onc.1202657
– ident: 2025032605451556000_8.2.e001392.51
  doi: 10.1016/j.canlet.2011.06.006
– ident: 2025032605451556000_8.2.e001392.9
  doi: 10.1016/S0140-6736(15)01281-7
– ident: 2025032605451556000_8.2.e001392.14
  doi: 10.1038/cdd.2013.67
– ident: 2025032605451556000_8.2.e001392.59
  doi: 10.1158/0008-5472.CAN-14-3098
– ident: 2025032605451556000_8.2.e001392.56
  doi: 10.1042/BST20130156
– volume: 65
  start-page: 1089
  year: 2005
  ident: 2025032605451556000_8.2.e001392.8
  article-title: Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity
  publication-title: Cancer Res
  doi: 10.1158/0008-5472.1089.65.3
– ident: 2025032605451556000_8.2.e001392.18
  doi: 10.1016/j.cllc.2015.07.002
– ident: 2025032605451556000_8.2.e001392.25
  doi: 10.1038/nri.2016.107
– ident: 2025032605451556000_8.2.e001392.10
  doi: 10.1056/NEJMoa1501824
– ident: 2025032605451556000_8.2.e001392.22
  doi: 10.1164/rccm.201207-1180OC
– ident: 2025032605451556000_8.2.e001392.30
  doi: 10.1038/ni.2035
– volume: 97
  start-page: 123
  year: 2017
  ident: 2025032605451556000_8.2.e001392.48
  article-title: Cytokines in immunogenic cell death: applications for cancer immunotherapy
  publication-title: Cytokine
  doi: 10.1016/j.cyto.2017.05.024
– ident: 2025032605451556000_8.2.e001392.5
  doi: 10.1634/theoncologist.2017-0078
– volume: 30
  start-page: 219
  year: 2019
  ident: 2025032605451556000_8.2.e001392.15
  article-title: Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors
  publication-title: Ann Oncol
  doi: 10.1093/annonc/mdy551
– ident: 2025032605451556000_8.2.e001392.42
  doi: 10.1038/nri3423
– volume: 16
  start-page: 341
  year: 2019
  ident: 2025032605451556000_8.2.e001392.3
  article-title: Comparing and contrasting predictive biomarkers for immunotherapy and targeted therapy of NSCLC
  publication-title: Nat Rev Clin Oncol
  doi: 10.1038/s41571-019-0173-9
– ident: 2025032605451556000_8.2.e001392.43
  doi: 10.1124/mol.115.099614
– volume: 11
  year: 2020
  ident: 2025032605451556000_8.2.e001392.45
  article-title: Npm1 upregulates the transcription of PD-L1 and suppresses T cell activity in triple-negative breast cancer
  publication-title: Nat Commun
  doi: 10.1038/s41467-020-15364-z
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Snippet BackgroundThe immune checkpoint blockade (ICB) targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) has been proved beneficial for numerous types of...
The immune checkpoint blockade (ICB) targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) has been proved beneficial for numerous types of cancers,...
Background The immune checkpoint blockade (ICB) targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) has been proved beneficial for numerous types...
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SubjectTerms Antibodies
Basic Tumor Immunology
Blood & organ donations
Cancer
Cancer therapies
Chemotherapy
Cold
combination
costimulatory and inhibitory t-cell receptors
Cytokines
drug therapy
Immunotherapy
Kinases
Lung cancer
Lymphocytes
Monoclonal antibodies
Reactive oxygen species
tumor escape
tumor microenvironment
Tumors
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Title Antimetabolite pemetrexed primes a favorable tumor microenvironment for immune checkpoint blockade therapy
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