AUTHOR=Namkoong Hong , Lee Bomi , Swaminathan Gayathri , Koh Seong-Joon , Rogalla Stephan , Paraskevopoulou Maria D. , Tang Jay , Mikhail David , Becker Laren S. , Habtezion Aida 

TITLE=GPR15 in colon cancer development and anti-tumor immune responses

JOURNAL=Frontiers in Oncology

VOLUME=Volume 13 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1254307

DOI=10.3389/fonc.2023.1254307

ISSN=2234-943X

ABSTRACT=Abstract 
The chemoattractant receptor, G protein-coupled receptor 15 (GPR15) in response to its ligand, C10orf99/GPR15L, promotes colon homing of T cells in health and colitis. GPR15 function in colon cancer is largely unexplored, motivating our current studies using human colorectal cancer (CRC) tissues and murine colon cancer models. Our analysis of human CRC tissue revealed a significant reduction in GPR15+ immune cell frequencies in tumors compared to ‘tumor-free’ surgical margins. Furthermore, our analysis of data obtained from The Cancer Genome Atlas (TCGA) database indicated that lower GPR15 expression is associated with poor survival in human colon cancer. In the AOM/DSS colitis-associated murine colon cancer model, we observed increased colon polyps and lower survival in Gpr15-deficient (KO) compared to Gpr15-sufficient (Het) mice. Analysis of immune cell infiltrates in the colon polyps showed significantly decreased CD8+ T cells and increased IL-17+ CD4+ and IL-17+ CD8+ T cells in Gpr15-KO compared to Gpr15-Het mice. GPR15 deficiency thus alters the immune environment in colon polyps to mitigate T cell-mediated anti-tumor responses resulting in severe disease. Consistent with a protective role of GPR15, administration of GPR15L to established tumors in the MC38-CRC model dramatically reduced tumor burden. Our findings highlight an important role of the GPR15-GPR15L axis in promoting a tumor-suppressive immune microenvironment and unveils a novel, colon-specific therapeutic target for CRC.