Tumor-Intrinsic and Microenvironmental Determinants of Impaired Antitumor Immunity in Chromophobe Renal Cell Carcinoma
Chris Labaki, Eddy Saad, Katrine N. Madsen, Charbel Hobeika, Kevin Bi, Michel Alchoueiry, Sabrina Y. Camp, Yue Hou, Ziad Bakouny, Sayed Matar, Nourhan El Ahmar, Jackson Nyman, Long Zhang, Carmen Priolo, Rishabh Rout, Melissa Daou, Damir Khabibullin, S. Salem, Nicholas R. Schindler, Renée Maria Saliby, Kevin Meli, J. Connor Wells, Erica Pimenta, Kosuke Takemura, Jihye Park, Marc Eid, Karl Semaan, Jingxin Fu, Thomas Denize, Razane El Hajj Chehade, Marc Machaalani, Rashad Nawfal, Wassim Daoud Khatoun, Mustafa Saleh, Jad El Masri, Nina Rossa Haddad, Wenxin Xu, Bradley A. McGregor, Michelle S. Hirsch, Wanling Xie, Daniel Yick Chin Heng, David F. McDermott, Sabina Signoretti, Eliezer M. Van Allen, Sachet A. Shukla, Toni K. Choueiri, Elizabeth P. Henske, David A. Braun
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.