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

Abstract

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.

Distinct immune signatures are a potent tool in the clinical management of cytokine-related syndrome during immune checkpoint therapy

“…This is further supported by the elevated levels of IL-10, IL1-RA, CXCL9 and CXCL10 in cluster 1 with improved OS highlighting these markers as potential biomarkers of enhanced anti-tumor activity in ICI therapy. Specifically, these inflammatory chemokines bind to the CXCR3 receptor and specifically target activated T lymphocytes and natural killer (NK) cells (39)(40)(41).…”

Tumor Immunogenic Cell Death as a Mediator of Intratumor CD8 T-Cell Recruitment

“…More precisely, there is a higher CXCL9/10-CXCR3-pathway-score protein expression in responder patients. Altogether, this suggests that a higher CXCR3-CXCL9/10 axis activation results in a better response to immunotherapy in this setting [ 140 ]. In a French cohort of 60 stage III/IV advanced NSCLC from whom a plasma soluble factors analysis was conducted before an immunotherapy injection, we showed that higher CXCL10 levels were correlated with a better response to first-line treatment, consisting of platinum-based doublet chemotherapy.…”

Activation of the TGF-β Pathway Enhances the Efficacy of Platinum-Based Chemotherapy in Small Cell Lung Cancer Patients

“…For example, Zhou et al used the ssGSEA score of DDR and its subpathways, to investigate the effect of the DDR pathway activation status on the prognosis of patients with metastatic urothelial carcinoma [ 21 ]. Feng et al used ssGSEA to discover that a high activation status of the chemokine receptor 3 pathway presents as a potential prognostic predictor for patients treated with immune checkpoint inhibitors [ 22 ].…”