Type 1 conventional dendritic cells are systemically dysregulated early in pancreatic carcinogenesis

Type 1 conventional dendritic cells (cDC1s) are typically thought to be dysregulated secondarily to invasive cancer. Here, we report that cDC1 dysfunction instead develops in the earliest stages of preinvasive pancreatic intraepithelial neoplasia (PanIN) in the KrasLSL-G12D/+ Trp53LSL-R172H/+ Pdx1-C...

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Published inThe Journal of experimental medicine Vol. 217; no. 8
Main Authors Lin, Jeffrey H., Huffman, Austin P., Wattenberg, Max M., Walter, David M., Carpenter, Erica L., Feldser, David M., Beatty, Gregory L., Furth, Emma E., Vonderheide, Robert H.
Format Journal Article
LanguageEnglish
Published United States Rockefeller University Press 03.08.2020
Subjects
Aged
Animals
Carcinogenesis - genetics
Carcinogenesis - immunology
Carcinogenesis - pathology
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - pathology
Dendritic Cells - immunology
Dendritic Cells - pathology
Female
Humans
Male
Mice
Middle Aged
Neoplasm Proteins - genetics
Neoplasm Proteins - immunology
Neoplasms, Experimental - genetics
Neoplasms, Experimental - immunology
Neoplasms, Experimental - pathology
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - immunology
Pancreatic Neoplasms - pathology
Tumor Immunology
Online AccessGet full text
ISSN0022-1007
1540-9538
1540-9538
DOI10.1084/jem.20190673

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Abstract Type 1 conventional dendritic cells (cDC1s) are typically thought to be dysregulated secondarily to invasive cancer. Here, we report that cDC1 dysfunction instead develops in the earliest stages of preinvasive pancreatic intraepithelial neoplasia (PanIN) in the KrasLSL-G12D/+ Trp53LSL-R172H/+ Pdx1-Cre–driven (KPC) mouse model of pancreatic cancer. cDC1 dysfunction is systemic and progressive, driven by increased apoptosis, and results in suboptimal up-regulation of T cell–polarizing cytokines during cDC1 maturation. The underlying mechanism is linked to elevated IL-6 concomitant with neoplasia. Neutralization of IL-6 in vivo ameliorates cDC1 apoptosis, rescuing cDC1 abundance in tumor-bearing mice. CD8+ T cell response to vaccination is impaired as a result of cDC1 dysregulation. Yet, combination therapy with CD40 agonist and Flt3 ligand restores cDC1 abundance to normal levels, decreases cDC1 apoptosis, and repairs cDC1 maturation to drive superior control of tumor outgrowth. Our study therefore reveals the unexpectedly early and systemic onset of cDC1 dysregulation during pancreatic carcinogenesis and suggests therapeutically tractable strategies toward cDC1 repair.
AbstractList Type 1 conventional dendritic cells (cDC1s) are typically thought to be dysregulated secondarily to invasive cancer. Here, we report that cDC1 dysfunction instead develops in the earliest stages of preinvasive pancreatic intraepithelial neoplasia (PanIN) in the KrasLSL-G12D/+ Trp53LSL-R172H/+ Pdx1-Cre-driven (KPC) mouse model of pancreatic cancer. cDC1 dysfunction is systemic and progressive, driven by increased apoptosis, and results in suboptimal up-regulation of T cell-polarizing cytokines during cDC1 maturation. The underlying mechanism is linked to elevated IL-6 concomitant with neoplasia. Neutralization of IL-6 in vivo ameliorates cDC1 apoptosis, rescuing cDC1 abundance in tumor-bearing mice. CD8+ T cell response to vaccination is impaired as a result of cDC1 dysregulation. Yet, combination therapy with CD40 agonist and Flt3 ligand restores cDC1 abundance to normal levels, decreases cDC1 apoptosis, and repairs cDC1 maturation to drive superior control of tumor outgrowth. Our study therefore reveals the unexpectedly early and systemic onset of cDC1 dysregulation during pancreatic carcinogenesis and suggests therapeutically tractable strategies toward cDC1 repair.
Type 1 conventional dendritic cells are progressively and systemically dysregulated during pancreatic carcinogenesis, subject to semimaturation and IL-6–driven apoptosis. Yet, CD40 agonist synergizes with Flt3L to rescue cDC1 abundance and maturation, enabling a return to full CD8 + T cell priming. Type 1 conventional dendritic cells (cDC1s) are typically thought to be dysregulated secondarily to invasive cancer. Here, we report that cDC1 dysfunction instead develops in the earliest stages of preinvasive pancreatic intraepithelial neoplasia (PanIN) in the Kras LSL- G12D/+ Trp53 LSL- R172H/+ Pdx1-Cre –driven (KPC) mouse model of pancreatic cancer. cDC1 dysfunction is systemic and progressive, driven by increased apoptosis, and results in suboptimal up-regulation of T cell–polarizing cytokines during cDC1 maturation. The underlying mechanism is linked to elevated IL-6 concomitant with neoplasia. Neutralization of IL-6 in vivo ameliorates cDC1 apoptosis, rescuing cDC1 abundance in tumor-bearing mice. CD8 + T cell response to vaccination is impaired as a result of cDC1 dysregulation. Yet, combination therapy with CD40 agonist and Flt3 ligand restores cDC1 abundance to normal levels, decreases cDC1 apoptosis, and repairs cDC1 maturation to drive superior control of tumor outgrowth. Our study therefore reveals the unexpectedly early and systemic onset of cDC1 dysregulation during pancreatic carcinogenesis and suggests therapeutically tractable strategies toward cDC1 repair.
Type 1 conventional dendritic cells (cDC1s) are typically thought to be dysregulated secondarily to invasive cancer. Here, we report that cDC1 dysfunction instead develops in the earliest stages of preinvasive pancreatic intraepithelial neoplasia (PanIN) in the KrasLSL-G12D/+ Trp53LSL-R172H/+ Pdx1-Cre-driven (KPC) mouse model of pancreatic cancer. cDC1 dysfunction is systemic and progressive, driven by increased apoptosis, and results in suboptimal up-regulation of T cell-polarizing cytokines during cDC1 maturation. The underlying mechanism is linked to elevated IL-6 concomitant with neoplasia. Neutralization of IL-6 in vivo ameliorates cDC1 apoptosis, rescuing cDC1 abundance in tumor-bearing mice. CD8+ T cell response to vaccination is impaired as a result of cDC1 dysregulation. Yet, combination therapy with CD40 agonist and Flt3 ligand restores cDC1 abundance to normal levels, decreases cDC1 apoptosis, and repairs cDC1 maturation to drive superior control of tumor outgrowth. Our study therefore reveals the unexpectedly early and systemic onset of cDC1 dysregulation during pancreatic carcinogenesis and suggests therapeutically tractable strategies toward cDC1 repair.Type 1 conventional dendritic cells (cDC1s) are typically thought to be dysregulated secondarily to invasive cancer. Here, we report that cDC1 dysfunction instead develops in the earliest stages of preinvasive pancreatic intraepithelial neoplasia (PanIN) in the KrasLSL-G12D/+ Trp53LSL-R172H/+ Pdx1-Cre-driven (KPC) mouse model of pancreatic cancer. cDC1 dysfunction is systemic and progressive, driven by increased apoptosis, and results in suboptimal up-regulation of T cell-polarizing cytokines during cDC1 maturation. The underlying mechanism is linked to elevated IL-6 concomitant with neoplasia. Neutralization of IL-6 in vivo ameliorates cDC1 apoptosis, rescuing cDC1 abundance in tumor-bearing mice. CD8+ T cell response to vaccination is impaired as a result of cDC1 dysregulation. Yet, combination therapy with CD40 agonist and Flt3 ligand restores cDC1 abundance to normal levels, decreases cDC1 apoptosis, and repairs cDC1 maturation to drive superior control of tumor outgrowth. Our study therefore reveals the unexpectedly early and systemic onset of cDC1 dysregulation during pancreatic carcinogenesis and suggests therapeutically tractable strategies toward cDC1 repair.
Author Vonderheide, Robert H.
Lin, Jeffrey H.
Wattenberg, Max M.
Carpenter, Erica L.
Feldser, David M.
Huffman, Austin P.
Walter, David M.
Beatty, Gregory L.
Furth, Emma E.
AuthorAffiliation 6 Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
5 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
4 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
1 Immunology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
2 Cell and Molecular Biology Graduate Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
3 Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
AuthorAffiliation_xml – name: 2 Cell and Molecular Biology Graduate Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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– name: 1 Immunology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
– name: 3 Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
– name: 6 Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/32453421$$D View this record in MEDLINE/PubMed
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Disclosures: E.L. Carpenter reported personal fees from Imedex, personal fees from AstraZeneca, grants from Janssen, grants from Merck, and grants from Becton Dickinson outside the submitted work. G.L. Beatty reported personal fees from Seattle Genetics, personal fees from Aduro Biotech, personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb, personal fees from Genmab, personal fees from Merck, personal fees from Shattuck Labs, personal fees from Boehinger Ingelheim, personal fees from BiolineRx, personal fees from Incyte, grants from Arcus Biosciences, grants from Verastem, grants from Halozyme, grants from Biothera, grants from Newlink, grants from Janssen, grants from Bristol-Myers Squibb, and grants from Incyte outside the submitted work; in addition, G.L. Beatty had a patent to 10577417 with royalties paid "Novartis, U of Pennsylvania." R.H. Vonderheide reported personal fees from Celgene, personal fees from Celldex, personal fees from Janssen, personal fees from Lilly, personal fees from Medimmune, personal fees from Verastem, grants from Apexigen, grants from Fibrogen, grants from Inovio, grants from Janssen, and grants from Lilly outside the submitted work; in addition, R.H. Vonderheide had a patent to cellular immunotherapy licensed "Novartis" and a patent to VLA-4 research antibody licensed "BD Pharmigen." No other disclosures were reported.
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PublicationTitle The Journal of experimental medicine
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32697286 - J Exp Med. 2020 Aug 3;217(8)
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Snippet Type 1 conventional dendritic cells (cDC1s) are typically thought to be dysregulated secondarily to invasive cancer. Here, we report that cDC1 dysfunction...
Type 1 conventional dendritic cells are progressively and systemically dysregulated during pancreatic carcinogenesis, subject to semimaturation and IL-6–driven...
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SubjectTerms Aged
Animals
Carcinogenesis - genetics
Carcinogenesis - immunology
Carcinogenesis - pathology
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - pathology
Dendritic Cells - immunology
Dendritic Cells - pathology
Female
Humans
Male
Mice
Middle Aged
Neoplasm Proteins - genetics
Neoplasm Proteins - immunology
Neoplasms, Experimental - genetics
Neoplasms, Experimental - immunology
Neoplasms, Experimental - pathology
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - immunology
Pancreatic Neoplasms - pathology
Tumor Immunology
Title Type 1 conventional dendritic cells are systemically dysregulated early in pancreatic carcinogenesis
URI https://www.ncbi.nlm.nih.gov/pubmed/32453421
https://www.proquest.com/docview/2406942778
https://pubmed.ncbi.nlm.nih.gov/PMC7398166
Volume 217
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