Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer resistant to immunotherapy. We create a PDA mouse model and show that neoantigen expression is required for intratumoral T cell accumulation and response to immune checkpoint blockade. By generating a peptide:MHC tetramer, we identify that PDA induces rapid intratumoral, and progressive systemic, tumor-specific T cell exhaustion. Monotherapy PD-1 or PD-L1 blockade enhances systemic T cell expansion and induces objective responses that require systemic T cells. However, tumor escape variants defective in IFNγ-inducible Tap1 and MHC class I cell surface expression ultimately emerge. Combination PD-1 + PD-L1 blockade synergizes therapeutically by increasing intratumoral KLRG1+Lag3-TNFα+ tumor-specific T cells and generating memory T cells capable of expanding to spontaneous tumor recurrence, thereby prolonging animal survival. Our studies support that PD-1 and PD-L1 are relevant immune checkpoints in PDA and identify a combination for clinical testing in those patients with neoantigen-specific T cells.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2140-2155.e6 |
| Journal | Cell reports |
| Volume | 28 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 20 2019 |
Bibliographical note
Funding Information:We thank Dr. Pamela Rosato for help generating the CB tetramer. We thank the NIH Tetramer Core for generously supplying us with fluorescently labeled Ova 257–264 :H-2K b tetramer. We thank Dr. Jason Mitchell at the Center for Immunology (CFI) for initial help with microscopy. We thank colleagues at the CFI at the University of Minnesota for helpful discussions. A.L.B. is supported by a computational training award from the American Association of Immunologists . E.J.S. is supported in part by an Alpha Omega Alpha Carolyn L. Kuckein Student Research Fellowship. I.W. is part of the Wayzata High Schools Honors Mentor Connection Program in Minnesota. M.O. is supported by the University of Minnesota Undergraduate Research Opportunities Program (UROP). I.M.S. is supported by an American Association for Cancer Research (AACR) Pancreatic Cancer Action Network Career Development Award ( 17-20-25-STRO ), an Institutional Research Grant ( 124166-IRG-58-001-55-IRG65 ) from the American Cancer Society , and support from the Masonic Cancer Center ( University of Minnesota Medical School ).
Funding Information:
We thank Dr. Pamela Rosato for help generating the CB tetramer. We thank the NIH Tetramer Core for generously supplying us with fluorescently labeled Ova257?264:H-2Kb tetramer. We thank Dr. Jason Mitchell at the Center for Immunology (CFI) for initial help with microscopy. We thank colleagues at the CFI at the University of Minnesota for helpful discussions. A.L.B. is supported by a computational training award from the American Association of Immunologists. E.J.S. is supported in part by an Alpha Omega Alpha Carolyn L. Kuckein Student Research Fellowship. I.W. is part of the Wayzata High Schools Honors Mentor Connection Program in Minnesota. M.O. is supported by the University of Minnesota Undergraduate Research Opportunities Program (UROP). I.M.S. is supported by an American Association for Cancer Research (AACR) Pancreatic Cancer Action Network Career Development Award (17-20-25-STRO), an Institutional Research Grant (124166-IRG-58-001-55-IRG65) from the American Cancer Society, and support from the Masonic Cancer Center (University of Minnesota Medical School). I.M.S. and A.L.B. designed the study, analyzed the data, and wrote the manuscript. A.L.B. E.S. J.F.R. I.W. and M.O. conducted experiments and analyzed data. I.M.S. supervised the study and is guarantor of the study. The authors declare no competing interests.
Publisher Copyright:
© 2019 The Author(s)
Keywords
- PD-1
- PD-L1
- PDA
- T cells
- acquired resistance
- immunotherapy
- neoepitope
- pancreatic cancer
PubMed: MeSH publication types
- Journal Article
