Targeting CCR1 Remodels the Tumor Microenvironment and Relieves Immunosuppression in Pancreatic Cancer.

Abstract

A hallmark of pancreatic cancer is an extensive fibroinflammatory stroma. Myeloid cells, including abundant macrophages, are a prevalent cellular component of the pancreatic cancer microenvironment and a key driver of immunosuppression. Identifying mechanisms of myeloid cell-driven immunosuppression is thus key to developing therapeutic approaches. Harnessing single-cell RNA sequencing data from human and murine tumors, we determined that tumor-infiltrating myeloid cells (including macrophages and granulocytes) have elevated expression of C-C motif chemokine receptor 1 (CCR1). To determine the functional role of CCR1, we generated oncogenic KRAS-based genetically engineered mouse models of pancreatic cancer, with or without the addition of a mutant form of the tumor suppressor Trp53 (KC and KPC, respectively), lacking CCR1 expression. CCR1 inactivation did not affect the formation of early lesions but delayed progression to cancer and resulted in prolonged survival. In these mice, macrophages lacking CCR1 had reduced expression of the immunosuppressive marker arginase 1. Loss of CCR1 also profoundly shifted the prevalent fibroblast population, inducing a pancreatic stellate cell-like phenotype. In two independent syngeneic orthotopic models, ablation or pharmacologic inhibition of CCR1 reduced tumor growth and increased CD8+ T-cell cytotoxic activity, sensitizing tumors to immunotherapy. Our data show that CCR1-expressing myeloid cells promote pancreatic cancer growth through modulation of the immune microenvironment and fibroblasts, indicating that CCR1 might be a suitable target for combination therapy.