COX-2 regulates IL-17A-producing γδ T cells to drive mismatch repair-deficient colon cancer

Among colorectal cancers (CRC), DNA mismatch repair-deficient (dMMR) tumors exhibit high mutational burden, increased immunogenicity, and better responsiveness to immune checkpoint blockade, when compared to MMR-proficient (pMMR) tumors. As a result, conventional T cells have been extensively studied in this disease, while the function of gδ T cells is understudied. Here, we report on a novel dMMR CRC mouse model whose cancer progression relies on IL-17A-producing gδ T cells. Deletion of Mlh1 in mouse intestinal epithelial cells resulted in tumors with a long latency period and high mutational burden. Mlh1 -deficient tumors were characterized by inflammatory transcriptional signatures. IL-17A-producing gδ T cells were the most abundant T cell in these tumors, and deletion or inhibition of these cells extended survival of tumor-bearing mice, indicative of their pro-tumorigenic role. Interfering with gδ T cells or IL-17A increased CD8 T cell and reduced neutrophil infiltration into tumors. Mlh1 -deficient tumors were unresponsive to anti-PD-1 immunotherapy. Resistance to this immunotherapy was facilitated by IL-17A-producing gδ T cells. However, tumors were sensitive to COX-2 inhibition, as celecoxib extended survival and reduced tumor-associated gδ T cells. Analysis of human CRC indicated that gδ T cells are more frequent in dMMR than pMMR and exhibit activation of IL-17 pathway. Tumor-associated macrophages exhibited the highest expression of PTGS2 , mirroring observations in mice. This study demonstrates that IL-17A-producing gδ T cells under regulation of COX-2 play an important role in dMMR CRC progression, revealing potential new targets for immunotherapy-resistant dMMR tumors.