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. 2025 Feb;6(2):372-384.
doi: 10.1038/s43018-024-00896-w. Epub 2025 Jan 9.

Immunogenomic determinants of exceptional response to immune checkpoint inhibition in renal cell carcinoma

Tejas Jammihal #  1   2 , Renee Maria Saliby #  3   4 , Chris Labaki #  3   5 , Hanna Soulati  4 , Juan Gallegos  2 , Arnau Peris  2 , Dustin McCurry  2 , Chunlei Yu  2 , Valisha Shah  3 , Deepak Poduval  4 , Talal El Zarif  3 , Nourhan El Ahmar  6 , Yasmin Nabil Laimon  6 , Marc Eid  3 , Aseman Bagheri Sheshdeh  6 , Katherine M Krajewski  7   8 , Florian A Büttner  9   10 , Matthias Schwab  9   10   11 , Daniel Heng  12 , Rafael C Casellas  2 , Kunal Rai  13 , Niki M Zacharias Millward  14 , Pavlos Msaouel  15 , Jose Karam  14 , Sabina Signoretti  6 , Eliezer Van Allen  3 , Toni K Choueiri  16 , David A Braun  17 , Sachet A Shukla  18
Affiliations

Immunogenomic determinants of exceptional response to immune checkpoint inhibition in renal cell carcinoma

Tejas Jammihal et al. Nat Cancer. 2025 Feb.

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.

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Conflict of interest statement

Competing interests: D.H. reports consulting and research funding from BMS, Ipsen, Novartis, Pfizer, Merck, Eisai and EMD Serono. P.M. reports honoraria for service on a scientific advisory board for Mirati Therapeutics, BMS and Exelixis, consulting for Axiom Healthcare Strategies, nonbranded educational programs supported by Exelixis and Pfizer and research funding for clinical trials from Takeda, BMS, Mirati Therapeutics, Gateway for Cancer Research and the University of Texas MD Anderson Cancer Center. S.S. reports commercial research grants from BMS, AstraZeneca, Exelixis and Novartis, is a consultant or advisory board member for Merck, AstraZeneca, BMS, CRISPR Therapeutics AG, AACR and NCI, receives royalties from Biogenex and mentors several non-US citizens on research projects with potential funding (in part) from non-US sources or foreign components. E.V.A. reports advisory or consulting roles for Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Manifold Bio, Monte Rosa, Novartis Institute for Biomedical Research, Riva Therapeutics and Serinus Bio, research support from Novartis, BMS and Sanofi, equity in Tango Therapeutics, Genome Medical, Genomic Life, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa, Riva Therapeutics and Serinus Bio, institutional patents filed on chromatin mutations and immunotherapy response and methods for clinical interpretation, intermittent legal consulting on patents for Foaley & Hoag and editorial board membership for JCO Precision Oncology and Science Advances. T.K.C. reports institutional and/or personal, paid and/or unpaid support for research, advisory boards, consultancy and/or honoraria from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, BMS, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date and CME events (Peerview, OncLive, MJH, CCO and others) outside the submitted work, institutional patents filed on molecular alterations and immunotherapy response/toxicity and ctDNA, equity in Tempest, Pionyr, Osel, Precede Bio, CureResponse and InnDura, committee membership for NCCN, GU Steering Committee, ASCO/ESMO, ACCRU and KidneyCan, potential medical writing and editorial assistance support funded by communications companies and mentorship of several non-US citizens on research projects with potential funding (in part) from non-US sources or foreign components. Dana-Farber Cancer Institute may have received additional independent funding from drug companies and/or royalties potentially involved in research around the subject matter. D.A.B. reports honoraria from LM Education/Exchange Services, advisory board fees from Exelixis and AVEO, consulting fees from Merck and Elephas, equity in Elephas, Fortress Biotech (subsidiary) and CurIOS Therapeutics, personal fees from Schlesinger Associates, Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, AbbVie, Accolade 2nd.MD, DLA Piper and Merck and research support from Exelixis and AstraZeneca outside of the submitted work. S.A.S. has equity in Agenus, Agios Pharmaceuticals, Breakbio, BMS, Imunon, Jivanu Therapeutics and Lumos Pharma and receives consulting fees from Imunon and Jivanu Therapeutics. The other authors declare no competing interests.

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