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

Nat Med. 2020 Jun;26(6):909-918. doi: 10.1038/s41591-020-0839-y. Epub 2020 May 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigen Presentation / genetics
  • Antineoplastic Agents, Immunological / therapeutic use*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / immunology
  • Carcinoma, Renal Cell / pathology
  • Chromosome Deletion
  • Chromosomes, Human, Pair 6
  • Chromosomes, Human, Pair 9 / genetics
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • DNA-Binding Proteins / genetics
  • Female
  • Fluorescent Antibody Technique
  • Gene Deletion
  • Genomics
  • Histocompatibility Antigens Class II / genetics
  • Histone Demethylases / genetics
  • Histone-Lysine N-Methyltransferase / genetics
  • Humans
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / immunology
  • Kidney Neoplasms / pathology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Male
  • Middle Aged
  • Mutation
  • Nivolumab / therapeutic use*
  • PTEN Phosphohydrolase / genetics
  • Prognosis
  • Proteasome Endopeptidase Complex / genetics
  • Sequence Analysis, RNA
  • TOR Serine-Threonine Kinases / genetics
  • Transcription Factors / genetics
  • Tuberous Sclerosis Complex 1 Protein / genetics
  • Tumor Suppressor Proteins / genetics
  • Ubiquitin Thiolesterase / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Whole Exome Sequencing

Substances

  • Antineoplastic Agents, Immunological
  • BAP1 protein, human
  • DNA-Binding Proteins
  • Histocompatibility Antigens Class II
  • PBRM1 protein, human
  • TSC1 protein, human
  • Transcription Factors
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins
  • Nivolumab
  • Histone Demethylases
  • KDM5C protein, human
  • Histone-Lysine N-Methyltransferase
  • SETD2 protein, human
  • Von Hippel-Lindau Tumor Suppressor Protein
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Ubiquitin Thiolesterase
  • Proteasome Endopeptidase Complex
  • VHL protein, human