Cited by 460Cancer Immunotherapy and BiomarkersPancreatic and Hepatic Oncology ResearchImmunotherapy and Immune Responses

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Induction of T-cell Immunity Overcomes Complete Resistance to PD-1 and CTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma

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Winograd, Rafael, Byrne, Katelyn T., Evans, Rebecca A., Odorizzi, Pamela M., Meyer, Anders R.L., Bajor, David L., Clendenin, Cynthia, Stanger, Ben Z., Furth, Emma E., Wherry, E. John, Vonderheide, Robert H.·2015·Cancer Immunology Research

DOI 10.1158/2326-6066.cir-14-0215PMC PMC4390506

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Abstract

Disabling the function of immune checkpoint molecules can unlock T-cell immunity against cancer, yet despite remarkable clinical success with monoclonal antibodies (mAb) that block PD-1 or CTLA-4, resistance remains common and essentially unexplained. To date, pancreatic carcinoma is fully refractory to these antibodies. Here, using a genetically engineered mouse model of pancreatic ductal adenocarcinoma in which spontaneous immunity is minimal, we found that PD-L1 is prominent in the tumor microenvironment, a phenotype confirmed in patients; however, tumor PD-L1 was found to be independent of IFNγ in this model. Tumor T cells expressed PD-1 as prominently as T cells from chronically infected mice, but treatment with αPD-1 mAbs, with or without αCTLA-4 mAbs, failed in well-established tumors, recapitulating clinical results. Agonist αCD40 mAbs with chemotherapy induced T-cell immunity and reversed the complete resistance of pancreatic tumors to αPD-1 and αCTLA-4. The combination of αCD40/chemotherapy plus αPD-1 and/or αCTLA-4 induced regression of subcutaneous tumors, improved overall survival, and conferred curative protection from multiple tumor rechallenges, consistent with immune memory not otherwise achievable. Combinatorial treatment nearly doubled survival of mice with spontaneous pancreatic cancers, although no cures were observed. Our findings suggest that in pancreatic carcinoma, a nonimmunogenic tumor, baseline refractoriness to checkpoint inhibitors can be rescued by the priming of a T-cell response with αCD40/chemotherapy. Cancer Immunol Res; 3(4); 399–411. ©2015 AACR.

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The dark side of immunotherapy: pancreatic cancer
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Authors: Winograd, R., Byrne, K. T., Evans, R. A., Odorizzi, P. M., Meyer, A. R. L., Bajor, D. L., Clendenin, C., Stanger, B. Z., Furth, E. E., Wherry, E. J., & Vonderheide, R. H.
Affiliations: University of Pennsylvania (US)
Corresponding author: Vonderheide, Robert H.
ORCID: Winograd, Rafael
Byrne, Katelyn T.
Odorizzi, Pamela M.
Meyer, Anders R.L.
Bajor, David L.
Clendenin, Cynthia
Stanger, Ben Z.
Furth, Emma E.
Wherry, E. John
Vonderheide, Robert H.
Venue: Cancer Immunology Research
Publisher: American Association for Cancer Research (AACR)
Published: 2015-04-01
Volume: 3
Issue: 4
Pages: 399-411
ISSN: 2326-6066 (ISSN-L)
2326-6074
DOI: 10.1158/2326-6066.cir-14-0215
PMC: PMC4390506
OpenAlex: W2132290857
Cited by: 459
References: 87
Citations by year: 2026: 18 · 2025: 24 · 2024: 27 · 2023: 44 · 2022: 42 · 2021: 78 · 2020: 53 · 2019: 51 · 2018: 40 · 2017: 37 · 2016: 33 · 2015: 11
FWCI: 17.76
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Cancer Immunology Research (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: University of Pennsylvania
York University
National Heart, Lung, and Blood Institute (T32HL007775, T32HL007439)
National Cancer Institute (T32CA009140, R01CA169123, P30CA016520)
National Institute of Allergy and Infectious Diseases (P01AI112521, U19AI082630)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: pancreatic ductal adenocarcinoma, anti-PD-1 therapy, CTLA-4 blockade, immune checkpoint inhibitors, treatment resistance, PD-L1, tumor microenvironment, T cell immunity, combination chemotherapy, tumor immunogenicity, immunological memory, genetically engineered mouse models
MeSH terms: Gemcitabine, Animals, Antibodies, Monoclonal, Antimetabolites, Antineoplastic, Combined Modality Therapy, Deoxycytidine, Female, Genetic Engineering, Humans, Immune Tolerance, Immunity, Cellular, Interferon-gamma, Lymphocyte Activation, Mice, Inbred C57BL, Pancreatic Neoplasms, T-Lymphocyte Subsets, CD40 Antigens, Carcinoma, Pancreatic Ductal, Xenograft Model Antitumor Assays, Cell Line, Tumor, Tumor Microenvironment, B7-H1 Antigen, CTLA-4 Antigen

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Induction of T-cell Immunity Overcomes Complete Resistance to PD-1 and CTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma

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