An increased CD25-positive intestinal regulatory T lymphocyte population is dependent upon Cox-2 activity in the Apc model.

Only mismatch repair (MMR)-deficient colorectal cancer (CRC) appears to respond well to programmed death (PD)-1 inhibition at the present time. Emerging evidence suggests a role for micro-environmental factors such as CD25 cells modulating response to PD-1 inhibition. In the Apc model of familial adenomatous polyposis (MMR-proficient CRC), increased Cyclooxygenase-2 (Cox-2) expression by cells which include alternatively activated mononuclear phagocytes promotes intestinal tumorigenesis by mechanisms which may include immune suppression. To gain insight into this, we compared regulatory T cell (T ) populations between Apc and wild-type mice prior to and after the phase of increased intestinal Cox-2-dependent prostaglandin E (PGE ) production. There was no difference in systemic T function or numbers between Apc and wild-type mice. However, increased numbers of small intestinal CD25 T were observed with increased Cox-2 activity in the absence of any difference in the expression of Tgf-β or Tslp between Apc and wild-type mice. Cox-2 inhibitor therapy (Celecoxib) reversed the increase in Apc intestinal CD25 T numbers, without decreasing numbers of CD25 systemic T . Forkhead box protein 3 (FoxP3 ) and Cox-2 cells were co-localized to the interstitium of adenomas of Apc mice. These results suggest selective dependence of an 'activated T ' phenotype on paracrine Cox-2 activity in Apc small intestine. For therapeutic potential, further studies are required to evaluate the relevance of these findings to human cancer as well as the functional significance of CD25 intestinal T in cancer.