Kevin Bi, Meng Xiao He, Ziad Bakouny, Abhay Kanodia, Sara Napolitano, Jingyi Wu, Grace Grimaldi, David A. Braun, Michael S. Cuoco, Angie Mayorga, Laura DelloStritto, Gabrielle Bouchard, John Steinharter, Alok K. Tewari, Natalie I. Vokes, Erin Shannon, Maxine Sun, Jihye Park, Steven L. Chang, Bradley A. McGregor, Rizwan Haq, Thomas Denize, Sabina Signoretti, Jennifer L. Guerriero, Sébastien Vigneau, Orit Rozenblatt-Rosen, Asaf Rotem, Aviv Regev, Toni K. Choueiri, Eliezer M. Van Allen.
Immune checkpoint blockade (ICB) results in durable disease control in a subset of patients with advancedrenal cell carcinoma (RCC), but mechanisms driving resistance are poorly understood. We characterize thesingle-cell transcriptomes of cancer and immune cells from metastatic RCC patients before or after ICBexposure. In responders, subsets of cytotoxic T cells express higher levels of co-inhibitory receptors andeffector molecules. Macrophages from treated biopsies shift toward pro-inflammatory states in responseto an interferon-rich microenvironment but also upregulate immunosuppressive markers. In cancer cells,we identify bifurcation into two subpopulations differing in angiogenic signaling and upregulation of immu-nosuppressive programs after ICB. Expression signatures for cancer cell subpopulations and immuneevasion are associated withPBRM1mutation and survival in primary and ICB-treated advanced RCC. Ourfindings demonstrate that ICB remodels the RCC microenvironment and modifies the interplay between can-cer and immune cell populations critical for understanding response and resistance to ICB