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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
Open accessPublished version of a preprint
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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“Not surprisingly, therefore, the first clinical hints of success at deploying immunotherapy in PDAC have thus come from regimens that combine chemotherapy with targeting of one or more additional nodes within the dysfunctional TME (myeloid cells, Tregs) in combination with immune checkpoint inhibitors286,287.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [287]
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PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
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Metadata
- 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
- Venue
- Cancer Immunology Research
- Published
- 2015-04-01
- Volume
- 3
- Issue
- 4
- Pages
- 399-411
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- 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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