[F31] Determinants of response to myeloid cell co-activation therapy in pancreatic ductal adenocarcinoma

Description

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers and has demonstrated striking resistance to currently approved immunotherapies. This resistance is driven by the immunosuppressive tumor microenvironment, which is primarily orchestrated by myeloid cells. However, myeloid cells are functionally pliable, and we have demonstrated that co-activation of myeloid cells with agonists targeting the pattern recognition receptor Dectin-1 and activating receptor CD40 drives durable tumor regression in mouse models of PDAC. Despite the strong synergy induced by Dectin-1 and CD40 coactivation, the mechanisms driving tumor regression remain undefined. We have found that while treatment response is CD8+ T cell dependent, classical mechanisms of T cell cytotoxicity are dispensable. We have also found that macrophages are a required component of response. A major knowledge gap which limits development of effective immunotherapies is that the essential elements of an effective anti-tumor immune response in PDAC are incompletely defined. This proposal will address this by determining how myeloid cell co-activation remodels the tumor microenvironment to overcome immunosuppression and enable T cell mediated tumor clearance. These mechanistic insights will inform rational immunotherapy combinations beyond Dectin-1/CD40 coactivation for PDAC and other immunotherapy-resistant solid tumors. The central hypothesis of this proposal is that co-activation of Dectin-1 and CD40 enhances antigen presentation and phagocytosis by tumor-associated macrophages, which coordinate MHC-independent tumor clearance by T cells. To address this, we will 1) define non-classical mechanisms of T cell mediated tumor clearance and 2) determine how activated tumor macrophage antigen presentation and phagocytosis impacts tumor regression and tumor microenvironment remodeling after Dectin-1 and CD40 coactivation therapy. In Aim 1 we will investigate CD8+ T cell recognition of stress ligands upregulated on tumor cells after treatment through the receptor NKG2D and subsequent FAS-ligand mediated induction of apoptosis in tumor cells. We will utilize genetic NKG2D-deficient mice and FAS-knockout tumor lines to evaluate how these factors impair tumor regression after treatment. In Aim 2, we will investigate the impact of activated macrophage antigen presentation and phagocytosis on treatment response using Lyz2-Cre;B2mfl/fl and Lyz2-Cre;Cd36fl/fl tumor bearing mice. We will perform flow cytometry and multiplexed immunohistochemistry to define the impact of the components in Aim 1 and Aim 2 on T cell infiltration and effector functions, tumor cell apoptosis, and macrophage phenotype after therapy. This proposal will provide training in immunology and cancer biology through close mentorship and skill development in advanced immunohistochemistry and flow cytometry methods and analysis. The facilities and expertise in cancer immunotherapy available at the University of Istituzione: UNIVERSITY OF PENNSYLVANIA PI: Anna Thickens Progetto: 1F31CA317795-01

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Source

Source: reporter.nih.gov