Clear cell renal cell carcinoma (ccRCC) is molecularly heterogeneous, immune infiltrated, and selectively sensitive to immune checkpoint inhibition (ICI). However, the joint tumor-immune states that mediate ICI response remain elusive. We develop spatially aware deep-learning models of tumor and immune features to learn representations of ccRCC tumors using diagnostic whole-slide images (WSIs) in untreated and treated contexts (n = 1,102 patients). We identify patterns of grade heterogeneity in WSIs not achievable through human pathologist analysis, and these graph-based "microheterogeneity" structures associate with PBRM1 loss of function and with patient outcomes. Joint analysis of tumor phenotypes and immune infiltration identifies a subpopulation of highly infiltrated, microheterogeneous tumors responsive to ICI. In paired multiplex immunofluorescence images of ccRCC, microheterogeneity associates with greater PD1 activation in CD8+ lymphocytes and increased tumor-immune interactions. Our work reveals spatially interacting tumor-immune structures underlying ccRCC biology that may also inform selective response to ICI.
Cell reports. Medicine. 2023 Sep 19 [Epub]
Jackson Nyman, Thomas Denize, Ziad Bakouny, Chris Labaki, Breanna M Titchen, Kevin Bi, Surya Narayanan Hari, Jacob Rosenthal, Nicita Mehta, Bowen Jiang, Bijaya Sharma, Kristen Felt, Renato Umeton, David A Braun, Scott Rodig, Toni K Choueiri, Sabina Signoretti, Eliezer M Van Allen
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Graduate Program in Systems Biology, Cambridge, MA, USA; Broad Institute, Cambridge, MA, USA., Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute, Cambridge, MA, USA; Harvard Graduate Program in Biological and Biomedical Sciences, Boston, MA, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute, Cambridge, MA, USA., Department of Informatics & Analytics, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute, Cambridge, MA, USA; Stanford University, Stanford, CA, USA., ImmunoProfile, Department of Pathology, Brigham & Women's Hospital and Dana-Farber Cancer Institute, Boston, MA, USA., Department of Informatics & Analytics, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA., Broad Institute, Cambridge, MA, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: .