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

Science
Authors
Keywords
Abstract

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.

Year of Publication
2018
Journal
Science
Volume
359
Issue
6377
Pages
801-806
Date Published
2018 Feb 16
ISSN
1095-9203
DOI
10.1126/science.aan5951
PubMed ID
29301960
PubMed Central ID
PMC6035749
Links
Grant list
KL2 TR001100 / TR / NCATS NIH HHS / United States
K08 CA188615 / CA / NCI NIH HHS / United States
K12 CA090628 / CA / NCI NIH HHS / United States
U24 CA224316 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States