51 Discovery of Exhausted CD8+ T-cell States Associated with Clinical Outcomes in Renal Cell Carcinoma

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Baseline tumor infiltration by exhausted T cells with a resident memory phenotype (Tex-rm) is significantly associated with worse progression-free survival in advanced renal cell carcinoma patients receiving immune checkpoint inhibitor therapies. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Zhaochen Ye; Soki Kashima; Rishabh Rout; Colin Laughlin; Nicholas Schindler; Ro Malik; Maxine Sun; Mustafa Saleh; G Lee; Wenxin Xu; Sabina Signoretti; Michael Hurwitz; Adebowale Adeniran; Peter Humphrey; Patrick Kenney; Bradley McGregor; Rana McKay; Toni Choueiri; David Braun

doi:10.1093/oncolo/oyag312.052

Key Points

To systematically identify functional CD8+ exhausted T-cell states linked to progression-free survival in patients with advanced renal cell carcinoma receiving immune checkpoint inhibitor regimens.
Integrated bulk RNA-sequencing data from baseline tumor samples across four major clinical trials (HCRN GU16-260, JAVELIN Renal 101, COSMIC-313, CheckMate 9ER; N=1,527 total; N=1,004 receiving ICI or ICI+TKI) with an in-house scRNA-seq reference of CD8+ T cells from 70 advanced RCC tumors.
Classified exhausted CD8+ T cells into four functional states using non-negative matrix factorization and correlated these states with progression-free survival using the machine learning tool Scissor after ComBat batch correction.
Identified a resident-memory-like exhausted T-cell state (Tex-rm) expressing ZNF683 and ITGAE that strongly associated with worse progression-free survival across all ICI monotherapy and ICI+TKI combination arms (permutation test p < 0.001).
Demonstrated that Tex-rm enrichment was specific to ICI-based therapy arms (ratio of observed to expected [Ro/e] = 1.37–2.33) and absent in TKI monotherapy arms.

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Implication

Secondary analysis of clinical trials reveals resident-memory exhausted T cells drive immunotherapy resistance in advanced renal cell carcinoma, highlighting a novel predictive biomarker.

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Cite This Study

Ye et al. (2026) studied this question.

synapsesocial.com/papers/6a993626636c6408cfa7f04a https://doi.org/10.1093/oncolo/oyag312.052

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51 Discovery of Exhausted CD8+ T-cell States Associated with Clinical Outcomes in Renal Cell Carcinoma

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51 Discovery of Exhausted CD8+ T-cell States Associated with Clinical Outcomes in Renal Cell Carcinoma

Key Points

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Implication

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