13/Overall, we identify an interplay in the RCC TME between TLS & ZNF683+ SLAMF7+ exhausted CD8+ T cells that contribute to clinical outcomes with PD-1 blockade. This may help predict response to current therapies and inform strategies to overcome resistance to PD-1 ICI.

12/Finally, we examined how TLS and tissue-resident exhausted CD8+ T cells impacted outcomes with nivo. Patients were grouped by median GES split: TLS hi/ZNF683 lo, TLS hi/ZN683 hi, TLS lo/ZNF683 lo, TLS lo/ZNF683 hi. Patients with TLS hi/ZNF683 lo had improved PFS and OS.

11/Further validation in the external CheckMate-025 RCC cohort showed the same trend in the nivo arm—higher GES in PD and worse PFS/OS. However, the GES score showed no associations with outcomes in the everolimus arm, highlighting the specificity to PD-1 blockade.

10/Using matched bulk and scRNA-seq, we generated a ZNF683+ SLAMF7+ GES specific to tissue-resident exhausted cells. In 81 independent HCRN trial samples, the GES was higher in PD vs. CR/PR and associated with worse clinical outcomes.

9/Functional studies showed that SLAMF7 activation reduced pro-inflammatory cytokine production and proliferation in human CD4+ and CD8+ T cells in vitro, suggesting a role in driving T cell dysfunction.

7/Single-cell analysis of 28,268 T cells identified a tissue-resident like ZNF683+ SLAMF7+ exhausted CD8+ population associated with worse objective response and PFS.

6/Bulk data showed enriched B cell-related genes & TLS signatures in responders, confirmed by multiplex IF in 19 patients.

3/ #MikeAtkins, #CathyWu @danafarber.bsky.social, and @braunmdphd.bsky.social @yalecancer.bsky.social for their unwavering support!