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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年1月9日

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  • Tejas Jammihal,
  • Renee Maria Saliby,
  • Chris Labaki,
  • Hanna Soulati,
  • Juan Gallegos,
  • Arnau Peris,
  • Dustin McCurry,
  • Chunlei Yu,
  • Valisha Shah,
  • Deepak Poduval,
  • Talal El Zarif,
  • Nourhan El Ahmar,
  • Yasmin Nabil Laimon,
  • Marc Eid,
  • Aseman Bagheri Sheshdeh,
  • Katherine M. Krajewski,
  • Florian A. Büttner,
  • Matthias Schwab,
  • Daniel Heng,
  • Rafael C. Casellas,
  • Kunal Rai,
  • Niki M. Zacharias Millward,
  • Pavlos Msaouel,
  • Jose Karam,
  • Sabina Signoretti,
  • Eliezer Van Allen,
  • Toni K. Choueiri,
  • David A. Braun,
  • Sachet A. Shukla

摘要

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.