Single-cell and spatial profiling identify three response trajectories to pembrolizumab and radiation therapy in triple negative breast cancer

• Published in: Cancer cell Vol. 42; no. 1; pp. 70 - 84.e8
• Main Authors: Shiao, Stephen L., Gouin, Kenneth H., Ing, Nathan, Ho, Alice, Basho, Reva, Shah, Aagam, Mebane, Richard H., Zitser, David, Martinez, Andrew, Mevises, Natalie-Ya, Ben-Cheikh, Bassem, Henson, Regina, Mita, Monica, McAndrew, Philomena, Karlan, Scott, Giuliano, Armando, Chung, Alice, Amersi, Farin, Dang, Catherine, Richardson, Heather, Shon, Wonwoo, Dadmanesh, Farnaz, Burnison, Michele, Mirhadi, Amin, Zumsteg, Zachary S., Choi, Rachel, Davis, Madison, Lee, Joseph, Rollins, Dustin, Martin, Cynthia, Khameneh, Negin H., McArthur, Heather, Knott, Simon R.V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.01.2024
• Subjects: Animals; Antibodies, Monoclonal, Humanized - therapeutic use; Breast cancer metastasis; CAR T cell; Combined Modality Therapy; disseminated tumor cells; Humans; Immunotherapy; Mice; T cell; TCR T cell; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - radiotherapy; tumor dormancy; tumor microenvironment; vaccine; disseminated tumor cells; vaccine; CAR T cell; tumor dormancy; T cell; immunotherapy; Breast cancer metastasis; TCR T cell; tumor microenvironment
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2023.12.012

Strategies are needed to better identify patients that will benefit from immunotherapy alone or who may require additional therapies like chemotherapy or radiotherapy to overcome resistance. Here we employ single-cell transcriptomics and spatial proteomics to profile triple negative breast cancer biopsies taken at baseline, after one cycle of pembrolizumab, and after a second cycle of pembrolizumab given with radiotherapy. Non-responders lack immune infiltrate before and after therapy and exhibit minimal therapy-induced immune changes. Responding tumors form two groups that are distinguishable by a classifier prior to therapy, with one showing high major histocompatibility complex expression, evidence of tertiary lymphoid structures, and displaying anti-tumor immunity before treatment. The other responder group resembles non-responders at baseline and mounts a maximal immune response, characterized by cytotoxic T cell and antigen presenting myeloid cell interactions, only after combination therapy, which is mirrored in a murine model of triple negative breast cancer. •12 distinct spatial districts described the immune and non-immune cells relationships•Two responder types were found, one with a pre-existing immune response•The second response type only exhibited an immune response after αPD1 and radiation•Non-responders lacked immune infiltrate both before and after therapy Shiao et al. reveals the phenotypic and spatial changes that occur in the tumor immune microenvironment following anti-PD-1 therapy and radiation in triple-negative breast cancer. They identify three spatial distributions that associate with early responders, late responders and non-responders.