Elucidating and overcoming T cell dysfunction in pancreatic cancer

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. However, the underlying mechanisms governing immune surveillance and resistance to a robust antitumor T cell response in pancreatic cancer are largely unknown. We are poised to identify how to safely promote T cell-mediated destruction of pancreatic cancer through 2 funded R01 applications and a collaborative P01 application. Our preliminary data support the hypothesis that immune- mediated pancreatic cancer eradication requires the following components: 1) a high affinity tumor specific T cell, 2) modification of suppressive intratumoral myeloid cells, and 3) overcoming chronic inflammatory and immunosuppressive signaling pathways. Notably our results demonstrate that developing combinatorial strategies to overcome endogenous T cell dysfunction in PDA may not be the same for enhancing cellular therapy using T cell receptor (TCR) engineered based approaches. Thus, the 3 funded projects are based on the development of highly faithful PDA animal models in which an endogenous or TCR engineered T cell response can be tracked longitudinally over time. The projects are aimed at uncovering novel mechanisms that interfere with the efficacy of combinatorial immunotherapies designed to engage the endogenous immunity (project 1) or TCR engineered T cell therapy (project 2 and 3). We will test novel combinatorial approaches to safely enhance the antitumor activity of a combination therapy that uses CD40 agonist, anti-PD-L1 (project 1) or abrogating TGFb signaling in TCR engineered T cells (Project 2) or the combination of TCR engineered T cell therapy and simultaneous modification of the desmoplastic tumor microenvironment (Project 3). Together the studies will identify characteristics of T cells and the tumor microenvironment that produce durable antitumor responses during immunotherapy.