Burrack et al. characterized the T cells in a pancreatic tumor model (KPC expressing a Click Beetle [CB] antigen) and found progressive loss of IFNγ and granzyme B, and increases in Tox and IL-10 in CB-specific T cells. IL27p28 correlated with poor OS in PDA patients and was progressively expressed in intratumoral CD45+ cells in the model. Agonistic anti-CD40 decreased IL-27-mediated IL-10 production in intratumoral myeloid and CD8+ T cells, and, in combination with anti-PD-L1, prolonged survival, cured 63% of PDA-bearing animals, and increased effector and tissue resident memory T cells (TRM); effects were further enhanced in Tnfrsf1a-/- hosts.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN 55414. Center for Immunology, University of Minnesota Medical School, Minneap
Author Info: (1) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN 55414. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN (2) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN 55414. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN (3) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN 55414. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN (4) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN 55414. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN (5) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN 55414. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN (6) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN 55414. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN (7) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN 55414. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN (8) Department of Immunology and Microbiology, University of Colorado Anschutz Medical Center, Aurora, CO 80045. (9) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN 55414; ingunn@umn.edu. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55414; and. Center for Genome Engineering, University of Minnesota Medical School, Minneapolis, MN 55414.
