Pancreatic cancer is a particularly lethal malignancy that resists immunotherapy. In this study, using a preclinical pancreatic cancer murine model, we demonstrate a progressive decrease in IFN-γ and granzyme B and a concomitant increase in Tox and IL-10 in intratumoral tumor-specific T cells. Intratumoral myeloid cells produced elevated IL-27, a cytokine that correlates with poor patient outcome. Abrogating IL-27 signaling significantly decreased intratumoral Tox + T cells and delayed tumor growth yet was not curative. Agonistic αCD40 decreased intratumoral IL-27-producing myeloid cells, decreased IL-10-producing intratumoral T cells, and promoted intratumoral Klrg1 +Gzmb + short-lived effector T cells. Combination agonistic αCD40+αPD-L1 cured 63% of tumor-bearing animals, promoted rejection following tumor rechallenge, and correlated with a 2-log increase in pancreas-residing tumor-specific T cells. Interfering with Ifngr1 expression in nontumor/host cells abrogated agonistic αCD40+αPD-L1 efficacy. In contrast, interfering with nontumor/host cell Tnfrsf1a led to cure in 100% of animals following agonistic αCD40+αPD-L1 and promoted the formation of circulating central memory T cells rather than long-lived effector T cells. In summary, we identify a mechanistic basis for T cell exhaustion in pancreatic cancer and a feasible clinical strategy to overcome it.
Bibliographical noteFunding Information:
This work was supported by a computational training award from the American Association of Immunologists (to A.L.B.). M.R.R. is supported by National Institutes of Health (NIH) T32 AI 007313. E.J.S. and T.D.M. are supported by NIH T35 AI118620. 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 AACR Pancreatic Cancer Action Network Catalyst Award (19-35-STRO), an American Cancer Society Institutional Research Grant (124166-IRG-58-001-55-IRG65), and pilot awards from the Masonic Cancer Center and Cancer Research Training Initiative (University of Minnesota Medical School).
Copyright © 2021 by The American Association of Immunologists, Inc.
- Antineoplastic Agents, Immunological/pharmacology
- B7-H1 Antigen/antagonists & inhibitors
- CD40 Antigens/agonists
- CD8-Positive T-Lymphocytes/immunology
- Carcinoma, Pancreatic Ductal/drug therapy
- Disease Models, Animal
- Drug Screening Assays, Antitumor
- Lymphocyte Activation/drug effects
- Lymphocytes, Tumor-Infiltrating/immunology
- Mice, Transgenic
- Myeloid Cells/drug effects
- Pancreatic Neoplasms/drug therapy
- Primary Cell Culture
- Tumor Cells, Cultured/transplantation
- Tumor Microenvironment/drug effects
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Journal Article
- Research Support, N.I.H., Extramural