iiinova — where your digital self keeps evolving

Reposted by @lenawirth.bsky.social

Itai Yanai @itaiyanai.bsky.social · 16/04/2025

Is there anything more fun than starting your talk with a walk-up song?! Thank you to the brilliant 3rd year Immunobiology PhD students at Yale who organized the '12th Yale Immunobiology Student Symposium' today. @sofivieto.bsky.social

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Reposted by @lenawirth.bsky.social

Kelly Street @kstreet.bsky.social · 25/02/2025

I'm proud to have been a part of the team that worked on this project! Miya, @lenawirth.bsky.social, and @braunmdphd.bsky.social are all brilliant collaborators and an incredibly fun group to talk science with!

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lenawirth.bsky.social @lenawirth.bsky.social · 25/02/2025

14/ @kidneycan.bsky.social @oncoalert.bsky.social @oncodaily.bsky.social @oncodaily.bsky.social Finally, we would like to thank the DOD CDMRP and the NCI for their support, and the Cancer Discovery @theaacr.bsky.social Editors and Reviewers for their exceptional guidance through the submission.

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lenawirth.bsky.social @lenawirth.bsky.social · 25/02/2025

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.

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lenawirth.bsky.social @lenawirth.bsky.social · 25/02/2025

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.

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lenawirth.bsky.social @lenawirth.bsky.social · 25/02/2025

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.

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lenawirth.bsky.social @lenawirth.bsky.social · 25/02/2025

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.

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lenawirth.bsky.social @lenawirth.bsky.social · 25/02/2025

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.

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lenawirth.bsky.social @lenawirth.bsky.social · 25/02/2025

8/Using established gene signatures, these cells were inferred to have high tumor specificity, despite their association with resistance. We further investigated SLAMF7 as a potential driver of ICI resistance.

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lenawirth.bsky.social @lenawirth.bsky.social · 25/02/2025

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.

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lenawirth.bsky.social @lenawirth.bsky.social · 25/02/2025

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

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lenawirth.bsky.social @lenawirth.bsky.social · 25/02/2025

5/define determinants of response and resistance. We analyzed bulk & single-cell transcriptomes of RCC tumors from treatment-naïve patients in the HCRN GU16-260 trial (@hoosiercancer.bsky.social) before and/or at resistance to nivo.

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lenawirth.bsky.social @lenawirth.bsky.social · 25/02/2025

4/ICI targeting PD-1/PD-L1 have transformed RCC treatment, yet most patients lack durable responses. While transcriptomic studies have advanced our understanding of the RCC TME, the role of individual cell populations in ICI resistance remains unclear, highlighting the need to

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lenawirth.bsky.social @lenawirth.bsky.social · 25/02/2025

2/ @yalecancer.bsky.social @danafarbernews.bsky.social @hoosiercancer.bsky.social Huge thanks to all the investigators listed below for their hard work in making this study possible—this was a true team effort! Most importantly, thank you to the patients and their families, and the senior authors

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