Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma

Kevin Bi; Meng Xiao He; Ziad Bakouny; Abhay Kanodia; Sara Napolitano; Jingyi Wu; Grace Grimaldi; David A Braun; Michael S Cuoco; Angie Mayorga; Laura DelloStritto; Gabrielle Bouchard; John Steinharter; Alok K Tewari; Natalie I Vokes; Erin Shannon; Maxine Sun; Jihye Park; Steven L Chang; Bradley A McGregor; Rizwan Haq; Thomas Denize; Sabina Signoretti; Jennifer L Guerriero; Sébastien Vigneau; Orit Rozenblatt-Rosen; Asaf Rotem; Aviv Regev; Toni K Choueiri; Eliezer M Van Allen

doi:10.1016/j.ccell.2021.02.015

Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma

Cancer Cell. 2021 May 10;39(5):649-661.e5. doi: 10.1016/j.ccell.2021.02.015. Epub 2021 Mar 11.

Authors

Kevin Bi¹, Meng Xiao He², Ziad Bakouny³, Abhay Kanodia¹, Sara Napolitano¹, Jingyi Wu¹, Grace Grimaldi¹, David A Braun⁴, Michael S Cuoco⁵, Angie Mayorga⁶, Laura DelloStritto⁶, Gabrielle Bouchard³, John Steinharter³, Alok K Tewari⁷, Natalie I Vokes⁸, Erin Shannon⁵, Maxine Sun³, Jihye Park⁸, Steven L Chang⁹, Bradley A McGregor³, Rizwan Haq⁸, Thomas Denize¹⁰, Sabina Signoretti¹¹, Jennifer L Guerriero¹², Sébastien Vigneau¹, Orit Rozenblatt-Rosen⁵, Asaf Rotem¹, Aviv Regev¹³, Toni K Choueiri⁷, Eliezer M Van Allen¹⁴

Affiliations

¹ 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.
² 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.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
⁴ 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.
⁵ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁹ Division of Urology, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹⁰ Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹¹ 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.
¹² Harvard Medical School, Boston, MA 02115, USA; Breast Tumor Immunology Laboratory, Women's Cancer Program, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹³ 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.
¹⁴ 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.

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.

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

Carcinoma, Renal Cell / immunology
Carcinoma, Renal Cell / pathology
Carcinoma, Renal Cell / therapy*
DNA-Binding Proteins / immunology
Humans
Immunologic Factors / immunology*
Immunotherapy* / methods
Kidney Neoplasms / immunology
Kidney Neoplasms / pathology
Kidney Neoplasms / therapy*
Transcription Factors / immunology
Tumor Microenvironment / immunology*

Substances

DNA-Binding Proteins
Immunologic Factors
PBRM1 protein, human
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding