Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma

• Published in: Science (American Association for the Advancement of Science) Vol. 359; no. 6377; pp. 801 - 806
• Main Authors: Miao, Diana, Margolis, Claire A, Gao, Wenhua, Voss, Martin H, Li, Wei, Martini, Dylan J, Norton, Craig, Bossé, Dominick, Wankowicz, Stephanie M, Cullen, Dana, Horak, Christine, Wind-Rotolo, Megan, Tracy, Adam, Giannakis, Marios, Hodi, Frank Stephen, Drake, Charles G, Ball, Mark W, Allaf, Mohamad E, Snyder, Alexandra, Hellmann, Matthew D, Ho, Thai, Motzer, Robert J, Signoretti, Sabina, Kaelin, Jr, William G, Choueiri, Toni K, Van Allen, Eliezer M
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 16.02.2018
• Subjects: Apoptosis; B7-H1 Antigen - antagonists & inhibitors; Cancer; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - therapy; Cell death; Chromatin remodeling; Chromosomal Proteins, Non-Histone - genetics; Clear cell-type renal cell carcinoma; Cohort Studies; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 protein; Cytokines; Cytotoxicity; Drugs; Exome - genetics; Gene expression; Gene Expression Profiling; Genomics; Humans; Hypoxia; Immune checkpoint inhibitors; Immunity; Immunosuppressive agents; Immunotherapy - methods; Inhibitors; Interferon; Janus kinase; Kidney cancer; Kidney Neoplasms - genetics; Kidney Neoplasms - therapy; Lymphocytes T; Metastases; Metastasis; Mutation; Narcotics; Patients; PD-1 protein; PD-L1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Regression analysis; Signaling; Sucrose; Sugar; SWI/SNF complex; Therapy; Transcription factors; Transcription Factors - genetics; Transducers; Tumor cells; Tumors
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aan5951

Immune checkpoint inhibitors targeting the programmed cell death 1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole-exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the gene ( = 0.012), which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-1 or PD-L1 (PD-1 ligand) blockade therapy alone or in combination with anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) therapies ( = 0.0071). Gene-expression analysis of PBAF-deficient ccRCC cell lines and -deficient tumors revealed altered transcriptional output in JAK-STAT (Janus kinase-signal transducers and activators of transcription), hypoxia, and immune signaling pathways. loss in ccRCC may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy.