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

TLDR

Immune checkpoint inhibitors targeting PD‑1 improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). The study aimed to identify genomic alterations in ccRCC that correlate with response to anti‑PD‑1 monotherapy by performing whole‑exome sequencing of metastatic tumors from 35 patients. Gene‑expression analysis of PBAF‑deficient ccRCC cell lines and tumors revealed altered transcriptional output in JAK‑STAT, hypoxia, and immune signaling pathways. Loss‑of‑function mutations in PBRM1 were associated with clinical benefit from PD‑1 blockade in metastatic ccRCC, a finding replicated in an independent cohort, indicating that PBRM1 loss modifies tumor transcriptional programs to enhance immune checkpoint responsiveness.

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 PBRM1 gene (P = 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 (P = 0.0071). Gene-expression analysis of PBAF-deficient ccRCC cell lines and PBRM1-deficient tumors revealed altered transcriptional output in JAK-STAT (Janus kinase-signal transducers and activators of transcription), hypoxia, and immune signaling pathways. PBRM1 loss in ccRCC may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy.