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Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell
David A Braun1,2,3, Yue Hou1,4, Ziad Bakouny1,2
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Abstract:
PD-1 blockade has transformed the management of advanced clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of the PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors from patients with advanced ccRCC enrolled in prospective clinical trials of treatment with PD-1 blockade by whole-exome and RNA sequencing, integrated with immunofluorescence analysis, to uncover the immunogenomic determinants of the therapeutic response. Although conventional genomic markers (such as tumor mutation burden and neoantigen load) and the degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations associated with response or resistance to PD-1 blockade. These advanced ccRCC tumors were highly CD8+ T cell infiltrated, with only 27% having a non-infiltrated phenotype. Our analysis revealed that infiltrated tumors are depleted of favorable PBRM1 mutations and enriched for unfavorable chromosomal losses of 9p21.3, as compared with non-infiltrated tumors, demonstrating how the potential interplay of immunophenotypes with somatic alterations impacts therapeutic efficacy.
Insights
Chromosomal alterations, not tumor mutation burden, predict response to PD-1 blockade in advanced clear cell renal cell carcinoma (ccRCC). Favorable PBRM1 mutations and unfavorable 9p21.3 losses correlate with tumor immune infiltration and treatment efficacy.
Area of Science:
- Oncology
- Immunogenomics
- Genetics
Background:
- PD-1 blockade has revolutionized advanced clear cell renal cell carcinoma (ccRCC) treatment.
- Understanding the genomic and immunologic factors driving response and resistance is crucial.
Purpose of the Study:
- To identify immunogenomic determinants of response and resistance to PD-1 blockade in advanced ccRCC.
- To investigate the interplay between chromosomal alterations, immune infiltration, and therapeutic efficacy.
Main Methods:
- Whole-exome and RNA sequencing of 592 advanced ccRCC tumors from prospective clinical trials.
- Integrated immunofluorescence analysis.
- Correlation analysis of genomic markers, immune infiltration, and clinical response.
Main Results:
- Conventional markers like tumor mutation burden and neoantigen load did not correlate with clinical response.
- Specific chromosomal alterations were associated with response or resistance to PD-1 blockade.
- CD8+ T cell-infiltrated tumors showed depletion of PBRM1 mutations and enrichment of 9p21.3 losses compared to non-infiltrated tumors.
Conclusions:
- Chromosomal alterations are key determinants of PD-1 blockade efficacy in advanced ccRCC.
- The interplay between tumor immunophenotype and somatic alterations significantly impacts therapeutic outcomes.
- Findings highlight novel biomarkers for predicting response to immunotherapy in ccRCC.
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