RT Journal Article
SR Electronic
T1 GPR15 in colon cancer development and anti-tumor immune responses
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.13.435189
DO 10.1101/2021.03.13.435189
A1 Hong NamKoong
A1 Bomi Lee
A1 Gayathri Swaminathan
A1 Seong-Joon Koh
A1 Stephan Rogalla
A1 David Mikhail
A1 Aida Habtezion
YR 2021
UL http://biorxiv.org/content/early/2021/03/15/2021.03.13.435189.abstract
AB G protein-coupled receptor 15 (GPR15) is a chemoattractant receptor which in response to its ligand, C10orf99/GPR15L, promotes colon homing of T cells in health and colitis. The functional role of GPR15 in colon cancer is largely unexplored, motivating our current studies using murine colon cancer models and human colorectal cancer (CRC) tissues. Our initial analysis of human CRC specimen revealed significant reduction in GPR15 expression and frequency of GPR15+ immune cells in tumors compared to ‘tumor-free’ surgical margins. In the AOM/DSS murine model of colitis associated colon cancer (CAC), we observed increased colonic polyps/tumor burden and lower survival rate in Gpr15-deficient (KO) compared to Gpr15-sufficient (Het) mice. Analysis of immune cell infiltrates in the colonic polyps showed significantly decreased CD8+ T cells and increased IL-17+ CD4+ and IL-17+ CD8+ T cells in Gpr15-KO than in Het mice. GPR15 deficiency thus alters the immune environment in colonic 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 mouse model increased CD45+ cell infiltration, enhanced TNFα expression on CD4+ and CD8+ T cells at the tumor site and dramatically reduced tumor burden. Our findings highlight an important, unidentified role of the GPR15-GPR15L axis in promoting a tumor-suppressive immune microenvironment and unveils a novel, colon-specific therapeutic target for CRC.Competing Interest StatementThe authors have declared no competing interest.