Dual-loss of PBRM1 and RAD51 Identifies Hyper-sensitive Subset Patients to Immunotherapy in Clear Cell Renal Cell Carcinoma

Overview

Journal Cancer Immunol Immunother

Specialties Allergy & Immunology
Oncology
Pharmacology

Date 2024 Apr 12

PMID 38607586

Authors

Ziyang Xu

Wenbin Jiang

Li Liu

Youqi Qiu

Jiahao Wang

Siyuan Dai

Jianming Guo

Jiejie Xu

Affiliations

Soon will be listed here.

Abstract

Background: Homologous recombination deficiency (HRD), though largely uncharacterized in clear cell renal cell carcinoma (ccRCC), was found associated with RAD51 loss of expression. PBRM1 is the second most common mutated genes in ccRCC. Here, we introduce a HRD function-based PBRM1-RAD51 ccRCC classification endowed with diverse immune checkpoint blockade (ICB) responses.

Methods: Totally 1542 patients from four independent cohorts were enrolled, including our localized Zhongshan hospital (ZSHS) cohort and Zhongshan hospital metastatic RCC (ZSHS-mRCC) cohort, The Cancer Genome Atlas (TCGA) cohort and CheckMate cohort. The genomic profile and immune microenvironment were depicted by genomic, transcriptome data and immunohistochemistry.

Results: We observed that PBRM1-loss ccRCC harbored enriched HRD-associated mutational signature 3 and loss of RAD51. Dual-loss of PBRM1 and RAD51 identified patients hyper-sensitive to immunotherapy. This dual-loss subtype was featured by M1 macrophage infiltration. Dual-loss was, albeit homologous recombination defective, with high chromosomal stability.

Conclusions: PBRM1 and RAD51 dual-loss ccRCC indicates superior responses to immunotherapy. Dual-loss ccRCC harbors an immune-desert microenvironment but enriched with M1 macrophages. Dual-loss ccRCC is susceptible to defective homologous recombination but possesses high chromosomal stability.

Citing Articles

missense mutation delineate aggressive clear cell renal cell carcinoma subtype with favorable immunotherapeutic response.

Xu Z, Liu L, Jiang W, Qiu Y, Zhang B, Cheng J J Immunother Cancer. 2024; 12(10).

PMID: 39448203 PMC: 11499804. DOI: 10.1136/jitc-2024-009963.

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