Mechanisms of immunotherapy response and resistance in pancreatic ductal adenocarcinoma

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PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy including immune checkpoint blockade. Meanwhile, immunotherapy targeting the PD-1:PD-L1 pathway is inducing stunning clinical outcomes in other advanced malignancies. Despite decades of cancer immunology research, the underlying mechanisms governing immune surveillance in pancreas cancer are largely unknown. This is due, in part, to a lack of animal models that permit the detection of tumor-specific T lymphocytes during disparate clinical outcomes commonly observed in patients. We have filled this knowledge gap by creating novel animal models that permit the interrogation or the rare tumor-antigen specific T cells over time. Based on our recent discoveries, we are now uniquely poised to identify how to safely promote antigen-specific T cell-mediated destruction of pancreas cancer, and our proposal will use these results to develop a novel preclinical combination immune-based therapy to inform a clinical trial. Our compelling preliminary data support the hypothesis that immune-mediated pancreas cancer eradication requires a combination of a 1) high affinity tumor specific T cell, 2) modifying suppressive intratumoral myeloid cells, and 3) overcoming chronic inflammatory signaling mediated by TNFα. We screened a series of immunotherapies and identified that agonistic αCD40 or PD-L1 blockade has only transient antitumor activity whereas the combination leads to tumor eradication in 63% of animals. PD-L1 blockade failed to reinvigorate intratumoral T cell functions and instead changed the peripheral tumor-specific T cell repertoire and expands a unique peripheral T cell subpopulation enriched for pro-survival genes and Ikzf2. In contrast, agonistic αCD40 promotes potent, yet short-lived, cytolytic intratumoral T cells which correlates with a decrease in intratumoral myeloid cell IL-27 production. Finally, abrogating Tnfr1 expression by non-tumor/host cells overcomes tumor escape resulting in 100% of tumor eradication in αCD40+αPD-L1-treated animals. In Aim 1, we will identify the functional significance of the altered TCR repertoire and the Ikzf2+ T cell subpopulation induced following PD-L1 blockade. In Aim 2, we will test if agonistic αCD40 promotes potent cytolytic effector T cells by abrogating intratumoral myeloid cell production of IL-27 and/or CD8 T cell production of IL-10. In Aim 3, we will identify how IFNγ and TNFα signaling on non-tumor/host cells lead to disparate outcomes following combination immunotherapy of pancreas cancer and test a novel combinatorial immunotherapy that includes TNFα blockade in combination with a CD40 agonist and a PD-1 inhibitor. The studies are designed to identify a mechanistic basis for T cell dysfunction in pancreas cancer and to create a feasible clinical strategy to overcome it with the goal to create a safe and effective immune-based treatment for pancreas cancer patients.