Clear cell renal cell carcinomas (ccRCCs) are highly immune infiltrated, but the effect of immune heterogeneity on clinical outcome in ccRCC has not been fully characterized. Here we perform paired single-cell RNA (scRNA) and T cell receptor (TCR) sequencing of 167,283 cells from multiple tumor regions, lymph node, normal kidney, and peripheral blood of two immune checkpoint blockade (ICB)-naïve and four ICB-treated patients to map the ccRCC immune landscape. We detect extensive heterogeneity within and between patients, with enrichment of CD8A+ tissue-resident T cells in a patient responsive to ICB and tumor-associated macrophages (TAMs) in a resistant patient. A TCR trajectory framework suggests distinct T cell differentiation pathways between patients responding and resistant to ICB. Finally, scRNA-derived signatures of tissue-resident T cells and TAMs are associated with response to ICB and targeted therapies across multiple independent cohorts. Our study establishes a multimodal interrogation of the cellular programs underlying therapeutic efficacy in ccRCC.
Cancer cell. 2021 Apr 12 [Epub ahead of print]
Chirag Krishna, Renzo G DiNatale, Fengshen Kuo, Raghvendra M Srivastava, Lynda Vuong, Diego Chowell, Sounak Gupta, Chad Vanderbilt, Tanaya A Purohit, Ming Liu, Emily Kansler, Briana G Nixon, Ying-Bei Chen, Vladimir Makarov, Kyle A Blum, Kyrollis Attalla, Stanley Weng, Michael L Salmans, Mahdi Golkaram, Li Liu, Shile Zhang, Raakhee Vijayaraghavan, Traci Pawlowski, Victor Reuter, Maria I Carlo, Martin H Voss, Jonathan Coleman, Paul Russo, Robert J Motzer, Ming O Li, Christina S Leslie, Timothy A Chan, A Ari Hakimi
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA., Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Illumina, Inc., 5200 Illumina Way, San Diego, CA 92122, USA., Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, NY 10065, USA., Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: ., Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH 44195, USA; Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; National Center for Regenerative Medicine, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: ., Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: .