Vollmer et al. showed in muscle invasive bladder cancer (MIBC) that early-differentiated stem cell memory CD8+ T cells (TSCM), enriched in lymph nodes (LNs), are CXCR3hi. In vitro, CXCL11/10/9 induced TSCM migration and boosted antigen-specific TSCM expansion coincident with high expression of the CXCR3alt isoform. CXCR3 and CXCL11 abundance correlated with tumor drainage in LNs derived from patients with MIBC. High CXCL11 expression in biopsies from treatment-naive patients with MIBC correlated with high intratumoral T cell numbers, and combined CXCR3alt/CXCL11 evaluation strongly predicted MIBC response to neoadjuvant chemotherapy.
Contributed by Paula Hochman
ABSTRACT: 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-nave 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.
Author Info: (1) Institute of Medical Immunology, Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charit - Univ
Author Info: (1) Institute of Medical Immunology, Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. Berlin Center for Advanced Therapies (BeCAT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. (2) Institute of Medical Immunology, Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. (3) Institute of Medical Immunology, Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. Berlin Center for Advanced Therapies (BeCAT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. (4) Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. (5) Institute of Medical Immunology, Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. Berlin Center for Advanced Therapies (BeCAT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. (6) Department of Surgical and Perioperative Sciences, Urology and Andrology, Umea University, 901 85 Umea, Sweden. Department of Clinical Microbiology, Immunology, Umea University, 901 85 Umea, Sweden. (7) Institute of Medical Immunology, Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. Berlin Center for Advanced Therapies (BeCAT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. (8) Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. (9) Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. (10) Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. (11) Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. (12) Institute of Medical Immunology, Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. (13) Centre for Genomic Regulation, Barcelona Institute of Science and Technology, 08003 Barcelona, Spain. Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain. (14) Center for Translational Medicine, Medical Clinic I, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, D-44623 Herne, Germany. (15) Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. Center for Translational Medicine, Medical Clinic I, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, D-44623 Herne, Germany. (16) Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. Center for Translational Medicine, Medical Clinic I, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, D-44623 Herne, Germany. (17) Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. Berlin Center for Advanced Therapies (BeCAT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. (18) Department of Clinical Immunology, Karolinska University Hospital, 17 176 Stockholm, Sweden. (19) Department of Surgical and Perioperative Sciences, Urology and Andrology, Umea University, 901 85 Umea, Sweden. (20) Institute of Medical Immunology, Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. (21) Institute of Medical Immunology, Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. michael.schmueck-henneresse@charite.de. Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany. Berlin Center for Advanced Therapies (BeCAT), Charit - Universittsmedizin Berlin, D-13353 Berlin, Germany.
