Immune checkpoint therapy (ICT) can produce durable antitumor responses in metastatic urothelial carcinoma (mUCC); however, the responses are not universal. Despite multiple approvals of ICT in mUCC, we lack predictive biomarkers to guide patient selection.
The identification of biomarkers may require interrogation of both the tumor mutational status and the immune microenvironment. Through multi-platform immuno-genomic analyses of baseline tumor tissues, we identified the mutation of AT-rich interactive domain-containing protein 1A (ARID1A) in tumor cells and expression of immune cytokine CXCL13 in the baseline tumor tissues as two predictors of clinical responses in a discovery cohort (n = 31). Further, reverse translational studies revealed that CXCL13-/- tumor-bearing mice were resistant to ICT, whereas ARID1A knockdown enhanced sensitivity to ICT in a murine model of bladder cancer. Next, we tested the clinical relevance of ARID1A mutation and baseline CXCL13 expression in two independent confirmatory cohorts (CheckMate275 and IMvigor210). We found that ARID1A mutation and expression of CXCL13 in the baseline tumor tissues correlated with improved overall survival (OS) in both confirmatory cohorts (CheckMate275, CXCL13 data, n = 217; ARID1A data, n = 139, and IMvigor210, CXCL13 data, n = 348; ARID1A data, n = 275). We then interrogated CXCL13 expression plus ARID1A mutation as a combination biomarker in predicting response to ICT in CheckMate275 and IMvigor210. Combination of the two biomarkers in baseline tumor tissues suggested improved OS compared to either single biomarker. Cumulatively, this study revealed that the combination of CXCL13 plus ARID1A may improve prediction capability for patients receiving ICT.
Science translational medicine. 2020 Jul 17 [Epub]
Sangeeta Goswami, Yulong Chen, Swetha Anandhan, Peter M Szabo, Sreyashi Basu, Jorge M Blando, Wenbin Liu, Jan Zhang, Seanu Meena Natarajan, Liangwen Xiong, Baoxiang Guan, Shalini Singh Yadav, Abdel Saci, James P Allison, Matthew D Galsky, Padmanee Sharma
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Department of Translational Medicine, Bristol Myers Squibb, Princeton, NJ 08540, USA., Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai/Tisch Cancer Institute, New York, NY 10029, USA., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. .