T_H17 cells regulate chemokine expression in epithelial cells through C/EBPβ and dictate host sensitivity to colitis...

T_H17 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_H17 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_H17 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_H17 cytokines, epithelial chemokine expression, and immune cell infiltration through a C/EBPβ-mediated pathway.