Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.
Nature communications. 2021 Feb 05*** epublish ***
Ziad Bakouny, David A Braun, Sachet A Shukla, Wenting Pan, Xin Gao, Yue Hou, Abdallah Flaifel, Stephen Tang, Alice Bosma-Moody, Meng Xiao He, Natalie Vokes, Jackson Nyman, Wanling Xie, Amin H Nassar, Sarah Abou Alaiwi, Ronan Flippot, Gabrielle Bouchard, John A Steinharter, Pier Vitale Nuzzo, Miriam Ficial, Miriam Sant'Angelo, Juliet Forman, Jacob E Berchuck, Shaan Dudani, Kevin Bi, Jihye Park, Sabrina Camp, Maura Sticco-Ivins, Laure Hirsch, Sylvan C Baca, Megan Wind-Rotolo, Petra Ross-Macdonald, Maxine Sun, Gwo-Shu Mary Lee, Steven L Chang, Xiao X Wei, Bradley A McGregor, Lauren C Harshman, Giannicola Genovese, Leigh Ellis, Mark Pomerantz, Michelle S Hirsch, Matthew L Freedman, Michael B Atkins, Catherine J Wu, Thai H Ho, W Marston Linehan, David F McDermott, Daniel Y C Heng, Srinivas R Viswanathan, Sabina Signoretti, Eliezer M Van Allen, Toni K Choueiri
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA., Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA., Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA., Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA., Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada., Bristol-Myers Squibb, Princeton, NJ, USA., Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA., Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA., Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA., Beth Israel Deaconess Medical Center, Boston, MA, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. ., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. .