Myeloid cell driven immune suppression in pancreatic cancer

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY Pancreatic Ductal Adenocarcinoma (PDA) is a deadly disease with a poor five-year survival rate of 10%. PDA is the most common type of pancreatic cancer and it is characterized by a complex immune suppressive microenvironment, maintained through the cross-talk between tumor cells, cancer associated fibroblasts (CAFs), and tumor associated macrophages (TAMs). Myeloid cells are essential for pancreatic cancer tumor growth and progression. Importantly, the depletion of myeloid cells restores CD8+ T cell mediated anti-tumor immune responses. Our previous characterization of infiltrating myeloid cells in the neoplastic pancreas has revealed high levels of Arginase 1 (Arg1) in myeloid cells. Arg1 is an enzyme that depletes the amino acid L-arginine from the microenvironment and it is a signature marker of alternatively activated and tumor associated macrophages. Importantly, L-arginine is required for T cell activation. Depletion of L-arginine results in T cell cycle arrest and inhibition of T cell activation. An increase in Arginase levels has been reported also in other cancers, including lung, gastrointestinal, and bladder cancer. Thus, Arg1 expression in myeloid cells might be a key mediator of immune suppression. However, this possibility has not been investigated directly in pancreatic cancer. Based on these observations, I will test the hypothesis that Arg1 myeloid cells are a key contributor to PDA immunosuppression and mediate resistance to the anti-PD1 immune checkpoint therapy. To test this hypothesis, I propose to define the role of myeloid Arg1 in the establishment of immune suppression in PDA (SA1) and to determine the role of myeloid Arg1 on polarization and metabolic status of macrophages in PDA (SA2). I will use in vitro and in vivo approaches, including genetically engineered mouse models and pharmacologic approaches. The objective of this study is to provide novel insights into the role of Arg1 in pancreatic cancer. This proposal has immediate clinical relevance, since Arg1 inhibitors are currently being tested in clinical trials. The overall goal is to identify new therapeutic targets for combination therapy in pancreatic cancer.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Pancreatic cancer is a lethal disease with a complex immune suppressive microenvironment characterized by the crosstalk between tumor cells, myeloid cells, and cancer associated fibroblasts. Arginase 1 is highly expressed in infiltrating cancer immune cells and its expression is driven by oncogenic Kras expressing cancer cells. Here, I propose to study the role of myeloid Arginase 1 in the pancreatic tumor microenvironment.