The tumor immune microenvironment plays a critical role in cancer progression and response to immunotherapy in clear cell renal cell carcinoma (ccRCC), yet the composition and phenotypic states of immune cells in this tumor are incompletely characterized. We performed single-cell RNA and T cell receptor sequencing on 164,722 individual cells from tumor and adjacent non-tumor tissue in patients with ccRCC across disease stages: early, locally advanced, and advanced/metastatic. Terminally exhausted CD8+ T cells were enriched in metastatic disease and were restricted in T cell receptor diversity. Within the myeloid compartment, pro-inflammatory macrophages were decreased, and suppressive M2-like macrophages were increased in advanced disease. Terminally exhausted CD8+ T cells and M2-like macrophages co-occurred in advanced disease and expressed ligands and receptors that support T cell dysfunction and M2-like polarization. This immune dysfunction circuit is associated with a worse prognosis in external cohorts and identifies potentially targetable immune inhibitory pathways in ccRCC.
Cancer cell. 2021 Mar 09 [Epub ahead of print]
David A Braun, Kelly Street, Kelly P Burke, David L Cookmeyer, Thomas Denize, Christina B Pedersen, Satyen H Gohil, Nicholas Schindler, Lucas Pomerance, Laure Hirsch, Ziad Bakouny, Yue Hou, Juliet Forman, Teddy Huang, Shuqiang Li, Ang Cui, Derin B Keskin, John Steinharter, Gabrielle Bouchard, Maxine Sun, Erica M Pimenta, Wenxin Xu, Kathleen M Mahoney, Bradley A McGregor, Michelle S Hirsch, Steven L Chang, Kenneth J Livak, David F McDermott, Sachet A Shukla, Lars R Olsen, Sabina Signoretti, Arlene H Sharpe, Rafael A Irizarry, Toni K Choueiri, Catherine J Wu
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA., Harvard Medical School, Boston, MA 02215, USA; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA., Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA., Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark; Center for Genomic Medicine, Rigshospitalet - Copenhagen University Hospital, Copenhagen, Denmark., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Academic Hematology, University College London, London, UK., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA 02139, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA; Division of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA., Harvard Medical School, Boston, MA 02215, USA; Division of Urologic Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA., Harvard Medical School, Boston, MA 02215, USA; Division of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA., Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Harvard Medical School, Boston, MA 02215, USA; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School & Brigham and Women's Hospital, Boston, MA 02115, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: .