Faculty, Staff and Student Publications

Language

English

Publication Date

2-1-2025

Journal

Nature Cancer

DOI

10.1038/s43018-024-00896-w

PMID

39789182

PMCID

PMC12121501

PubMedCentral® Posted Date

2-1-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Immune checkpoint inhibitors can lead to 'exceptional', durable responses in a subset of persons. However, the molecular basis of exceptional response (ER) to immunotherapy in metastatic clear cell renal cell carcinoma (mccRCC) has not been well characterized. Here we analyzed pretherapy genomic and transcriptomic data in treatment-naive persons with mccRCC treated with standard-of-care immunotherapies: (1) combination of programmed cell death protein and ligand 1 (PD1/PDL1) and cytotoxic T lymphocyte-associated protein 4 inhibitors (IO/IO) or (2) combination of PD1/PDL1 and vascular endothelial growth factor (VEGF) receptor inhibitors (IO/VEGF). In the IO/IO cohort, clonal neoantigen load was significantly higher in persons with ER. In the IO/VEGF cohort, ER participants displayed strong enrichment of B cell receptor signaling-related pathways, tertiary lymphoid structure (TLS) signatures and evidence of increased metabolic activity. Our results suggest that ER may be related to clonal neoantigen-driven cytotoxic T cell responses and TLS formation in tumor microenvironments. Therapeutic combinations that elicit both T cell-directed and B cell-directed antitumor immunity may be important to achieve exceptional benefit to IO-based treatment in ccRCC.

Keywords

Humans, Carcinoma, Renal Cell, Immune Checkpoint Inhibitors, Kidney Neoplasms, Female, Male, Middle Aged, Immunotherapy, B7-H1 Antigen, Aged, Programmed Cell Death 1 Receptor, Tumor Microenvironment

Published Open-Access

yes

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