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

Dataset ID Technology Samples
EGAD00001006026 Illumina HiSeq 2500 53

Dataset Description

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.

Data Use Conditions


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Label Code Version Modifier
disease specific research DUO:0000007 2019-01-07 MONDO:0005086, MONDO:0005005, MONDO:0004992, MONDO:0005206, MONDO:0002367
health or medical or biomedical research DUO:0000006 2019-01-07