Research ArticleCancer

The intratumoral CXCR3 chemokine system is predictive of chemotherapy response in human bladder cancer

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Science Translational Medicine  13 Jan 2021:
Vol. 13, Issue 576, eabb3735
DOI: 10.1126/scitranslmed.abb3735

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Patients with cancer are frequently treated with chemotherapy, but it does not always work, and it is difficult to predict who will respond to the treatment. In addition to the direct effects of chemotherapy, antitumor immune responses can also play an important role. By examining the immune responses in patients with muscle-invasive bladder cancer, Vollmer et al. identified a key role for the CXCR3 chemokine system of ligands and receptors. The activity of this system before initiation of treatment was associated with subsequent response to chemotherapy in multiple independent cohorts of patients, suggesting a potential rational approach to the selection of therapies.


Chemotherapy has direct toxic effects on cancer cells; however, long-term cancer control and complete remission are likely to involve CD8+ T cell immune responses. To study the role of CD8+ T cell infiltration in the success of chemotherapy, we examined patients with muscle invasive bladder cancer (MIBC) who were categorized on the basis of the response to neoadjuvant chemotherapy (NAC). We identified the intratumoral CXCR3 chemokine system (ligands and receptor splice variants) as a critical component for tumor eradication upon NAC in MIBC. Through characterization of CD8+ T cells, we found that stem-like T cell subpopulations with abundant CXCR3alt, a variant form of the CXCL11 receptor, responded to CXCL11 in culture as demonstrated by migration and enhanced effector function. In tumor biopsies of patients with MIBC accessed before treatment, CXCL11 abundance correlated with high numbers of tumor-infiltrating T cells and response to NAC. The presence of CXCR3alt and CXCL11 was associated with improved overall survival in MIBC. Evaluation of both CXCR3alt and CXCL11 enabled discrimination between responder and nonresponder patients with MIBC before treatment. We validated the prognostic role of the CXCR3-CXCL11 chemokine system in an independent cohort of chemotherapy-treated and chemotherapy-naïve patients with MIBC from data in TCGA. In summary, our data revealed stimulatory activity of the CXCR3alt-CXCL11 chemokine system on CD8+ T cells that is predictive of chemotherapy responsiveness in MIBC. This may offer immunotherapeutic options for targeted activation of intratumoral stem-like T cells in solid tumors.

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