AUTHOR=Choi Sung Hee , Huang Alex Y. , Letterio John J. , Kim Byung-Gyu 

TITLE=Smad4-deficient T cells promote colitis-associated colon cancer via an IFN-γ-dependent suppression of 15-hydroxyprostaglandin dehydrogenase

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.932412

DOI=10.3389/fimmu.2022.932412

ISSN=1664-3224

ABSTRACT=Immune cells and the cytokines they produce are important mediators of the transition from colitis to colon cancer, but the mechanisms mediating this disease progression are poorly understood. IFN-gamma is a major cytokine in colitis pathogenesis, but in the context of the disease, considerations have almost exclusively been restricted to its immune-modulatory and epithelial-directed functions. Here we explore whether IFN-gamma influences tumor progression by expanding effector memory T cells (TEM) population and restricting the expression of tumor suppressors in a preclinical model of spontaneous colitis-associated colorectal cancer (CAC). We show that IFN-gamma expression is significantly increased in the T cells and colon of mice with a T cell-restricted deletion of the TGF-β intermediate, SMAD4 (Smad4TKO). An increase of IFN-gamma expression correlates with the onset of spontaneous CAC in Smad4TKO mice by 6 months of age. This phenotype is greatly ameliorated by the introduction of a germline deletion of IFN-gamma in Smad4TKO mice (Smad4TKO/IFN-gKO, DKO). DKO mice had a significantly reduced incidence and progression of CAC, and a decrease in the number of mucosal CD4+ TEM cells, as compared to those of Smad4TKO. Similarly, the colon epithelia of DKO mice exhibited a non-oncogenic signature with a decrease in the expression of iNOS and p-STAT1, and a restoration of the tumor suppressor gene, 15-PGDH. In vitro treatment of human colon cancer cell culture with IFN-gamma decreased the expression of 15-PGDH. Our data suggest that IFN-gamma produced by activated TEM promotes epithelial malignancy by suppressing the expression of tumor suppressor genes.