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Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell RCC -- CA209-010

Immune checkpoint inhibitors targeting the PD-1 pathway have transformed the management of many advanced malignancies, including clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors collected from advanced ccRCC patients enrolled in prospective clinical trials of treatment with PD-1 blockade (or mTOR inhibition as control arm) by whole-exome and RNA-sequencing, integrated with immunofluorescence analysis, to define the somatic alteration landscape of late-stage ccRCC and to uncover the immunogenomic determinants of therapeutic response. While conventional genomic markers (tumor mutation burden, neoantigen load) and degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations in advanced ccRCC associated with response or resistance to PD-1 blockade. These advanced tumors were highly CD8+ T cell infiltrated, with only 22% and 5% with an immune desert and immune excluded phenotype, respectively. Our analysis revealed that CD8+ infiltrated tumors are depleted of favorable PBRM1 mutations and are enriched for unfavorable chromosomal losses of 9p21.3 when compared to non-infiltrated tumors. These data demonstrate how the interplay of somatic alterations and immunophenotypes impacts therapeutic efficacy.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001006026 Illumina HiSeq 2500 53
Publications Citations
Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma.
Nat Med 26: 2020 909-918
Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma.
Nat Commun 12: 2021 808
Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma.
Cancer Cell 39: 2021 649-661.e5
FCER1G positively relates to macrophage infiltration in clear cell renal cell carcinoma and contributes to unfavorable prognosis by regulating tumor immunity.
BMC Cancer 22: 2022 140
Genomic, epigenomic, and transcriptomic signatures for telomerase complex components: a pan-cancer analysis.
Mol Oncol 17: 2023 150-172
Epigenomic charting and functional annotation of risk loci in renal cell carcinoma.
Nat Commun 14: 2023 346
Spatially aware deep learning reveals tumor heterogeneity patterns that encode distinct kidney cancer states.
Cell Rep Med 4: 2023 101189