Tumor-Intrinsic and Microenvironmental Determinants of Impaired Antitumor Immunity in Chromophobe Renal Cell Carcinoma
Abstract
PURPOSE While immune checkpoint inhibition (ICI) has transformed the management of many advanced renal cell carcinomas (RCCs), the determinants of effective antitumor immunity for chromophobe RCC (ChRCC) and renal oncocytic tumors remain an unmet clinical and scientific need. METHODS Single-cell transcriptomic and T-cell receptor profiling was performed on tumor and adjacent normal tissue of patients with ChRCC and renal oncocytic neoplasms. Using machine learning, the cellular origin of renal oncocytic neoplasms was evaluated, with analysis of associated oncogenic pathways. Using immunohistochemistry, immune infiltration was analyzed in renal oncocytic neoplasms in comparison with clear cell RCC (ccRCC). Immune checkpoint expression, clonal expansion, and tumor specificity were compared between ChRCC and ccRCC. Using the International Metastatic RCC Database Consortium data set, clinical outcomes of patients with metastatic ChRCC (mChRCC) treated with first-line systemic regimens were compared with those of patients with ccRCC. RESULTS We validated α-intercalated cells as the cellular origin of renal oncocytic neoplasms. We identified a downregulation of HLA class I molecules with enrichment of potentially targetable pathways including mammalian target of rapamycin and ferroptosis in ChRCC. The tumor microenvironment of ChRCC showed markedly decreased immune infiltration, with a pronounced depletion in tumor-infiltrating CD8 + T cells. ChRCC-infiltrating CD8 + T cells demonstrated lower immune checkpoint expression, diminished clonal expansion, and decreased tumor specificity. Clinical analysis identified poor survival outcomes selectively among patients with mChRCC treated with immune-based therapies. CONCLUSION Immunogenomic analysis of ChRCC revealed profound depletion of T cells, with an immune phenotype marked by a lack of expression of immune checkpoints and poor tumor specificity, suggesting that the few T cells in these tumor types are likely nonspecific bystanders. This immune-cold environment hinders an effective response to immunotherapy and underscores the need for ChRCC-tailored treatments designed to improve tumor-specific T-cell infiltration into the microenvironment.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (48)
Chris Labaki
Beth Israel Deaconess Medical Center, Boston, MA
Eddy Saad
Katrine N. Madsen
Center of Molecular and Cellular Oncology (CMCO), Yale School of Medicine, New Haven, CT
Charbel Hobeika
Department of Medicine, Cleveland Clinic Fairview Hospital, Cleveland, OH
Kevin Bi
Michel Alchoueiry
Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
Sabrina Camp
Yue Hou
Department of Mechanical Engineering
Ziad Bakouny
Memorial Sloan Kettering Cancer Center
Sayed Matar
Nourhan El Ahmar
Jackson Nyman
PathAI, Inc, Boston, MA
Long Zhang
Carmen Priolo
Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
Rishabh Rout
Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT
Melissa Daou
Department of Medicine, Yale University, New Haven, CT
Damir Khabibullin
Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
Samer Salem
Cleveland Clinic, Cleveland, OH
Nicholas Schindler
Center of Molecular and Cellular Oncology (CMCO), Yale School of Medicine, New Haven, CT
Renee Maria Saliby
Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT
Kevin Meli
J. Connor Wells
Arthur JE Child Comprehensive Cancer Centre, Calgary, AB, Canada
Erica Pimenta
Kosuke Takemura
Faculty of Economics, Shiga University
Jihye Park
Department of Chemistry
Marc Eid
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Karl Semaan
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Jingxin Fu
Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616, United States
Thomas Denize
Department of Pathology, Massachusetts General Hospital, Boston
Razane El Hajj Chehade
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Marc Machaalani
Rashad Nawfal
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Wassim Daoud Khatoun
Dana-Farber Cancer Institute, Boston, MA
Mustafa Saleh
Jad El Masri
Nina Rossa Haddad
Wenxin Xu
Department of Medical Oncology Dana‐Farber Cancer Institute Boston Massachusetts USA
Bradley A. McGregor
Michelle S. Hirsch
Wanling Xie
Department of Medical Oncology Dana‐Farber Cancer Institute Boston Massachusetts USA
Daniel Y.C. Heng
Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada
David F. McDermott
Division of Medical Oncology, Department of Medicine Beth Israel Deaconess Medical Center Boston Massachusetts USA
Sabina Signoretti
Eliezer M. Van Allen
Sachet A. Shukla
Toni K. Choueiri
Department of Medical Oncology Dana‐Farber Cancer Institute Boston Massachusetts USA
Elizabeth P. Henske
Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
David A. Braun