PD-1 blockade has transformed the management of advanced clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of the PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors from patients with advanced ccRCC enrolled in prospective clinical trials of treatment with PD-1 blockade by whole-exome and RNA sequencing, integrated with immunofluorescence analysis, to uncover the immunogenomic determinants of the therapeutic response. Although conventional genomic markers (such as tumor mutation burden and neoantigen load) and the degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations associated with response or resistance to PD-1 blockade. These advanced ccRCC tumors were highly CD8+ T cell infiltrated, with only 27% having a non-infiltrated phenotype. Our analysis revealed that infiltrated tumors are depleted of favorable PBRM1 mutations and enriched for unfavorable chromosomal losses of 9p21.3, as compared with non-infiltrated tumors, demonstrating how the potential interplay of immunophenotypes with somatic alterations impacts therapeutic efficacy.
Nature medicine. 2020 May 29 [Epub ahead of print]
David A Braun, Yue Hou, Ziad Bakouny, Miriam Ficial, Miriam Sant' Angelo, Juliet Forman, Petra Ross-Macdonald, Ashton C Berger, Opeyemi A Jegede, Liudmilla Elagina, John Steinharter, Maxine Sun, Megan Wind-Rotolo, Jean-Christophe Pignon, Andrew D Cherniack, Lee Lichtenstein, Donna Neuberg, Paul Catalano, Gordon J Freeman, Arlene H Sharpe, David F McDermott, Eliezer M Van Allen, Sabina Signoretti, Catherine J Wu, Sachet A Shukla, Toni K Choueiri
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Harvard Medical School, Boston, MA, USA., Bristol-Myers Squibb, Princeton, NJ, USA., Broad Institute of MIT and Harvard, Cambridge, MA, USA., Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA., Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. ., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. ., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. .