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PMID: 33711272 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma.

Cancer cell ·Vol. 39 ·No. 5 ·2021-00-10 ·Pages 649-661.e5

Bi K, He MX, Bakouny Z, Kanodia A, Napolitano S, Wu J, Grimaldi G, Braun DA, Cuoco MS, Mayorga A, DelloStritto L, Bouchard G, Steinharter J, Tewari AK, Vokes NI, Shannon E, Sun M, Park J, Chang SL, McGregor BA, Haq R, Denize T, Signoretti S, Guerriero JL, Vigneau S, Rozenblatt-Rosen O, Rotem A, Regev A, Choueiri TK, Van Allen EM

Abstract

Immune checkpoint blockade (ICB) results in durable disease control in a subset of patients with advanced renal cell carcinoma (RCC), but mechanisms driving resistance are poorly understood. We characterize the single-cell transcriptomes of cancer and immune cells from metastatic RCC patients before or after ICB exposure. In responders, subsets of cytotoxic T cells express higher levels of co-inhibitory receptors and effector molecules. Macrophages from treated biopsies shift toward pro-inflammatory states in response to an interferon-rich microenvironment but also upregulate immunosuppressive markers. In cancer cells, we identify bifurcation into two subpopulations differing in angiogenic signaling and upregulation of immunosuppressive programs after ICB. Expression signatures for cancer cell subpopulations and immune evasion are associated with PBRM1 mutation and survival in primary and ICB-treated advanced RCC. Our findings demonstrate that ICB remodels the RCC microenvironment and modifies the interplay between cancer and immune cell populations critical for understanding response and resistance to ICB.

Keywords
cancer immunotherapy kidney resistance single cell
MeSH Terms
Carcinoma, Renal Cell/immunology,pathology,therapy DNA-Binding Proteins/immunology Humans Immunologic Factors/immunology Immunotherapy/methods Kidney Neoplasms/immunology,pathology,therapy Transcription Factors/immunology Tumor Microenvironment/immunology
Chemicals
DNA-Binding Proteins Immunologic Factors PBRM1 protein, human Transcription Factors
Authors & Affiliations
30 authors, click to expand affiliations / ORCID
Bi Kevin
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
He Meng Xiao
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Harvard Graduate Program in Biophysics, Boston, MA 02115, USA.
Bakouny Ziad
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Kanodia Abhay
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Napolitano Sara
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Wu Jingyi
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Grimaldi Grace
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Braun David A
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA.
Cuoco Michael S
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Mayorga Angie
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
DelloStritto Laura
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Bouchard Gabrielle
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Steinharter John
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Tewari Alok K
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
Vokes Natalie I
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Shannon Erin
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Sun Maxine
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Park Jihye
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Chang Steven L
Division of Urology, Brigham and Women's Hospital, Boston, MA 02115, USA.
McGregor Bradley A
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Haq Rizwan
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Denize Thomas
Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Signoretti Sabina
Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Guerriero Jennifer L
Harvard Medical School, Boston, MA 02115, USA; Breast Tumor Immunology Laboratory, Women's Cancer Program, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Vigneau Sébastien
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Rozenblatt-Rosen Orit
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Rotem Asaf
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Regev Aviv
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute and Koch Institute for Integrative Cancer Research, Department of Biology, MIT, Cambridge, MA 02139, USA.
Choueiri Toni K
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
Van Allen Eliezer M
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: eliezerm_vanallen@dfci.harvard.edu.
Conflict of Interest

Declaration of interests M.X.H. has consulted for Amplify Medicines and Ikena Oncology. Z.B. reports research support from Bristol-Meyers Squibb (BMS) and Genentech/imCORE unrelated to this study. D.A.B. reports non-financial support from BMS, honoraria from LM Education/Exchange Services, and personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, and Insight Strategy, outside of this work. B.A.M. has consulted for Bayer, Astellas, AstraZeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, and EMD Serono. He received research support to Dana-Farber Cancer Institute from BMS, Calithera, Exelixis, and Seattle Genetics. J.L.G. is a consultant for and/or receives sponsored research support from GlaxoSmithKline (GSK), Array BioPharma, Codagenix, Verseau, Kymera, and Eli Lilly. A. Rotem is an employee of AstraZeneca and an equity holder in NucleAI and Celsius Therapeutics. A. Regev is a founder and equity holder of Celsius Therapeutics, holds equity in Immunitas Therapeutics, and, until August 31, 2020, was an SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov, and Thermo Fisher Scientific; since August 1, 2020, she has been an employee of Genentech. E.M.V.A. reports advisory/consulting with Tango Therapeutics, Genome Medical, Invitae, Monte Rosa, Enara Bio, Manifold Bio, and Janssen; research support from Novartis and BMS; equity in Tango Therapeutics, Genome Medical, Syapse, Manifold Bio, Monte Rosa, and Enara Bio. T.K.C. reports research support/honoraria from, consulting/advisory relationships with, and/or equity stakes in Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, BMS, Calithera, Cerulean, Corvus, Eisai, EMD Serono, Exelixis, F. Hoffmann-La Roche, Foundation Management, Genentech, GSK, Heron Therapeutics, Infinity Pharma, Janssen Oncology, IQVIA, Ipsen, Lilly, Merck, NCCN, Novartis, Peloton, Pfizer, Pionyr, Prometheus Labs, Roche, Roche Products Limited, Sanofi/Aventis, Takeda, Tracon, Surface Oncology, Tempest, Up-to-Date, OncLIve, PVI, and MJH Life Sciences; patents filed, royalties, or other intellectual properties related to biomarkers of immune checkpoint blockers; and support from the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI.

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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccell.2021.02.015
Email
eliezerm_vanallen@dfci.harvard.edu
Published
2021-00-10
Epub
2021-00-11
Pages
649-661.e5
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC8115394
Subset
IM
Grants
NCI NIH HHS · U01 CA233100 · United States
NCI NIH HHS · P50 CA101942 · United States
NCI NIH HHS · T32 CA009172 · United States
NCI NIH HHS · R01 CA227388 · United States
NIGMS NIH HHS · T32 GM008313 · United States
NCI NIH HHS · U2C CA233195 · United States
Corrections
CommentIn
PMID: 33861995
External Links
PubMed source DOI: 10.1016/j.ccell.2021.02.015 PMC Full Text View journal details
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