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

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Exceptional responses to immune checkpoint inhibitors (ICIs) in metastatic clear cell renal cell carcinoma (mccRCC) are durable but poorly understood.
• The molecular drivers of exceptional response (ER) to immunotherapy in mccRCC remain to be fully elucidated.

Purpose of the Study:

• To investigate the molecular underpinnings of ER in treatment-naive mccRCC patients receiving standard-of-care immunotherapies.
• To identify distinct biological features associated with ER in different immunotherapy regimens.

Main Methods:

• Analysis of pretherapy genomic and transcriptomic data from mccRCC patients.
• Comparison of molecular profiles between patients with ER and non-ER in two distinct immunotherapy cohorts: PD1/PDL1 + CTLA4 inhibitors (IO/IO) and PD1/PDL1 + VEGF inhibitors (IO/VEGF).

Main Results:

• In the IO/IO cohort, ER was associated with a significantly higher clonal neoantigen load.
• In the IO/VEGF cohort, ER participants showed enrichment of B cell receptor signaling pathways, tertiary lymphoid structure (TLS) signatures, and increased metabolic activity.

Conclusions:

• Exceptional response in mccRCC may be driven by distinct mechanisms depending on the immunotherapy combination used.
• Clonal neoantigen-driven T cell responses and TLS formation appear crucial for ER in the IO/IO setting.
• B cell-directed immunity and increased tumor metabolic activity may contribute to ER in the IO/VEGF setting.
• Future therapeutic strategies should consider combinations that engage both T cell and B cell antitumor immunity for enhanced efficacy in ccRCC.