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. Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma.

Contact: kevinbi@broadinstitute.org

Immune checkpoint blockade (ICB) results in durable disease control in a subset of patients with advanced renal cell carcinoma (RCC), but mechanisms driving resistance are poorly understood. We characterize the single-cell transcriptomes of cancer and immune cells from metastatic RCC patients before or after ICB exposure. In responders, subsets of cytotoxic T cells express higher levels of co-inhibitory receptors and effector molecules. Macrophages from exposed biopsies shift towards pro-inflammatory states in response to 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 immunosuppressive programs after ICB. Expression signatures for cancer cell subpopulations and immune evasion are associated with PBRM1 mutation and survival in primary and ICB-treated advanced RCC. Our findings demonstrate that ICB remodels the RCC microenvironment and modifies the interplay between cancer and immune cell populations critical for understanding response and resistance to ICB.