Activation of the chemokine receptor 3 pathway leads to a better response to immune checkpoint inhibitors in patients with metastatic urothelial carcinoma.

Immune checkpoint inhibitors (ICIs) have made important breakthrough in anti-tumor therapy, however, no single biomarker can accurately predict their efficacy. Studies have found that tumor microenvironment is a key factor for determining the response to ICI therapy. Cytokine receptor 3 (C-X-C Motif Chemokine Receptor 3, CXCR3) pathway has been reported to play an important role in the migration, activation, and response of immune cells. We analyzed survival data, genomics, and clinical data from patients with metastatic urothelial carcinoma (mUC) who received ICI treatment to explore the relationship between CXCR3 pathway activation and the effectiveness of ICIs. The Cancer Genome Atlas Bladder Urothelial Carcinoma cohort and six other cohorts receiving ICI treatment were used for mechanism exploration and validation. In the ICI cohort, we performed univariate and multivariate COX analyses and discovered that patients in the CXCR3-high group were more sensitive to ICI treatment. A Kaplan-Meier analysis demonstrated that patients in the high CXCR3-high group had a better prognosis than those in the CXCR3-low group (P = 0.0001, Hazard Ratio = 0.56; 95% CI 0.42-0.75). CIBERSORT analysis found that mUC patients in the CXCR3-high group had higher levels of activated CD8+ T cells, M1 macrophages, and activated NK cells and less regulatory T cell (Treg) infiltration. Immunogenicity analysis showed the CXCR3-high group had higher tumor neoantigen burden (TNB). Our study suggests that CXCR3 pathway activation may be a novel predictive biomarker for the effectiveness of immunotherapy in mUC patients.