FARP1/RAC1/STAT3 Axis Circumvents CD8+ T Cell-Mediated Immunosurveillance by Restricting Antigen Presentation in Colorectal Cancer

Abstract

Colorectal cancer (CRC), the second deadliest cancer worldwide, shows increasing incidence and mortality rate among young individuals. Besides chemotherapy and targeted therapies, new agents targeting tumor microenvironment and immune cells are emerging. Particularly, immune checkpoint inhibitors (PD-1 and CTLA-4 mAbs) have successfully entered into CRC clinical care. However, only a relatively small population of CRC patients with DNA mismatch repair (MMR) defects harboring microsatellite instability (MSI) respond to the current therapies. Low mutation burden, leading to poor antigen presentation and CD8+ T cell cytotoxicity is a major culprit for immunotherapy resistance. Thus, the aim of this study was to harness a novel therapeutic target to render CRC cells more immunogenic. By applying the Inference of Cell Types and Deconvolution algorithm, we generated a gene library whose expression is negatively associated with relative cytotoxicity of CD8+ T cells in the tumor microenvironment of CRC patients. Given the central role of antigen presentation in mediating cytotoxicity of CD8+ T cells and its frequent downregulation in tumor cells, capacity of each gene to modulate antigen presentation was analyzed. Our findings identified that depletion of FARP1 significantly enhanced antigen presentation, promoted CD8+ T cell cytotoxicity, and profoundly suppressed tumor growth in preclinical models. Importantly, FARP1 is strongly upregulated in CRC patients. We showed that it restricts antigen presentation by activating RAC1 Rho GTPase and phosphorylating STAT3 to modulate transcription of antigen presentation and processing genes. Collectively, our findings suggest that FARP1/RAC1 axis is a potential therapeutic target for CRC immunotherapy.