Saturday, May 11, 2024
5/11/2024
Project Summary Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest human malignancies, with the 5-year survival rate currently at 12%. Little progress towards its treatment has been achieved over the past several decades. While treatment of malignancies such as lung cancer and melanoma have been revolutionized by immunotherapy, there has been little efficacy in pancreatic cancer patients. An immunosuppressive tumor microenvironment (TME) characterized by an abundance of cancer associated fibroblasts (CAFs) and immune- suppressive myeloid cells (IMCs), including tumor associated macrophages (TAMs) and myeloid-derived suppressor cells, is known to be a major barrier to effectively treating PDA. We have recently shown that KRAS, a major oncogenic driver in PDA, induces the expression of C-C Motif Chemokine Receptor 1 (CCR1) in pancreatic myeloid cells, and CCR1 ablation in mice inhibits pancreatic tumor growth by enhancing CD8+ T cell antitumor immunity. Loss of CCR1 in TAMs decreased secretion of itaconate, an immune modulatory metabolite that suppress proliferation and effector function of CD8+ T cells, and expression of Immune responsive gene 1 (IRG1), a myeloid-specific enzyme that produces itaconate. Our preliminary data also revealed that IRG1 ablation in orthotopic mouse model of PDA decreased tumor growth and enhanced CD8 T cell infiltration, supporting a critical role of IRG1/itaconate in regulating anti-tumor immunity in PDA. Based on these findings, we hypothesize that CCR1-IRG1 axis-dependent metabolic programming in myeloid cells contributes significantly to suppression of anti-tumor immunity in pancreatic cancer. In aim 1, we will dissect the mechanisms underlying fibroblast mediated metabolic regulation in IMCs through CCR1-IRG1 axis in PDA. Our preliminary data showed that pancreatic CAFs promoted expression of IRG1 in bone marrow derived macrophages. We will elucidate the fibroblast-derived CCLs and the CCR1-dependent signaling pathways in driving IRG1 expression and the immune suppressive phenotypes of IMCs using CAFs-IMCs co-cultures. In aim 2, we will characterize the contribution of IRG1 to the early carcinogenesis and development of pancreatic cancer using both mouse models and human pancreatic samples. In aim 3, we will explore targeting IRG1 in combination with immune checkpoint blockade and/or KRAS G12D inhibition as a therapeutic strategy using both pharmacological and genetic approaches. To achieve these aims, we have assembled a team of investigators with complementary expertise in human pathology and mouse models of PDA, immunometabolism, pancreatic surgery/immunology, and computational biology. Our study will not only provide critical insights into the immune suppressive function of the CCR1-IRG1 axis in PDA, but also identify novel therapeutic approaches to effectively treating PDA.
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