RESUMO
The immune escape of colon cancer and its role in the response to immunotherapies such as PD-1/PD-L1 checkpoint inhibitors have long been of great interest. The positive outcomes of immunotherapy are limited by the immunosuppressive nature of the tumor microenvironment. Integrin αvß6, which can regulate the progression of colon cancer, was recently reported to be involved in the immune suppression of colon cancer. In the present study, we explored the correlation between αvß6 and PD-L1 expression by immunohistochemistry of colon cancer tissues. Then, the regulation of PD-L1 signaling by αvß6 in colon cancer cells was demonstrated. We constructed an in vivo model and performed immunophenotyping experiments to analyze further the regulation of the immune response by αvß6. The role of αvß6 in the response to anti-PD-1 therapy in colon cancer was also verified. αvß6-positive tissues exhibited increased PD-L1 expression. Inhibition of αvß6 not only downregulated constitutive PD-L1 expression but also decreased IFN-γ-induced PD-L1 expression. In addition, αvß6-induced PD-L1 expression was suppressed by the ERK inhibitor PD98059, and knockdown of the ß6-ERK2 binding site had the equivalent effect. αvß6 decreased CD8+ T cell infiltration and granzyme B expression in CD8+ T cells in colon cancer patients. Furthermore, mice engrafted with αvß6-expressing colon cancer cells exhibited an unsatisfactory response to anti-PD-1 therapy, and anti-PD-1-induced increases in CD4+ and CD8+ T cell infiltration could be inhibited by αvß6. These results indicate that αvß6 mediates immune escape in colon cancer by upregulating PD-L1 through the ERK/MAPK pathway. Moreover, αvß6 could serve as a marker for the efficacy of anti-PD-1 therapy in colon cancer.