T(H)17 cells regulate chemokine expression in epithelial cells through C/EBPβ and dictate host sensitivity to colitis and cancer immunity.

T(H)17 cells play a critical role in inflammation, cancer development, and antitumor immunity in a context-dependent manner, but detailed mechanisms and their downstream signaling events remain poorly understood. Here, we describe that T(H)17 cytokines strongly inhibit expression of critical chemokines in epithelial tissues, which leads to blocking infiltration of proinflammatory immune cells into the colon, rendering resistance to DSS-induced colitis and colon cancer. We show that key chemokine expression dictates the sensitivity of WT mice to DSS treatment. Mechanistically, we identified C/EBPβ and STAT3 as negative regulators of key chemokine expression following IL-17 and IL-22 stimulation. Knockout of either C/EBPβ or STAT3 in mouse epithelial cells abolished the protective function of T(H)17 cytokines and converted resistant to sensitive phenotype. C/EBPβ ablation in cancer cells markedly enhanced chemokine expression, thus sensitizing cancer cells for anti-PD-1 immunotherapy. Overall, our findings have identified a previously unrecognized critical gap between T(H)17 cytokines, epithelial chemokine expression, and immune cell infiltration through a C/EBPβ-mediated pathway.