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

David A Braun; Yue Hou; Ziad Bakouny; Miriam Ficial; Miriam Sant' Angelo; Juliet Forman; Petra Ross-Macdonald; Ashton C Berger; Opeyemi A Jegede; Liudmilla Elagina; John Steinharter; Maxine Sun; Megan Wind-Rotolo; Jean-Christophe Pignon; Andrew D Cherniack; Lee Lichtenstein; Donna Neuberg; Paul Catalano; Gordon J Freeman; Arlene H Sharpe; David F McDermott; Eliezer M Van Allen; Sabina Signoretti; Catherine J Wu; Sachet A Shukla; Toni K Choueiri

doi:10.1038/s41591-020-0839-y

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.

Authors

David A Braun^{1

2

3}, Yue Hou^{1

4}, Ziad Bakouny^{1

2}, Miriam Ficial^{2

5}, Miriam Sant' Angelo^{2

5}, Juliet Forman^{1

3

4}, Petra Ross-Macdonald⁶, Ashton C Berger³, Opeyemi A Jegede⁷, Liudmilla Elagina³, John Steinharter¹, Maxine Sun¹, Megan Wind-Rotolo⁶, Jean-Christophe Pignon^{2

5}, Andrew D Cherniack^{1

2

3}, Lee Lichtenstein³, Donna Neuberg⁷, Paul Catalano^{2

7}, Gordon J Freeman^{1

2}, Arlene H Sharpe⁸, David F McDermott^{2

9}, Eliezer M Van Allen^{1

2

3}, Sabina Signoretti^#^{2

5

10}, Catherine J Wu^#^{11

12

13}, Sachet A Shukla^#^{14

15

16}, Toni K Choueiri^#^{17

18}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Harvard Medical School, Boston, MA, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA, USA.
⁵ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
⁶ Bristol-Myers Squibb, Princeton, NJ, USA.
⁷ Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
⁹ Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹⁰ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
¹² Harvard Medical School, Boston, MA, USA. [email protected].
¹³ Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
¹⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
¹⁵ Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
¹⁶ Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
¹⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
¹⁸ Harvard Medical School, Boston, MA, USA. [email protected].

^# Contributed equally.

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
Exome Sequencing
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

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
Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human
TOR Serine-Threonine Kinases
PTEN Phosphohydrolase
PTEN protein, human
Ubiquitin Thiolesterase
Proteasome Endopeptidase Complex
VHL protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding