ABSTRACT: 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.
Author Info: (1) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Elect
Author Info: (1) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address: stephen.shiao@cshs.org. (2) Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (3) Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (4) Breast Cancer Clinical Research Unit, Duke University Medical Center, Raleigh, NC, USA. Electronic address: alice.ho@duke.edu. (5) Ellison Institute of Technology, Los Angeles, CA, USA. (6) Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (7) Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (8) Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (9) Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (10) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (11) Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (12) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (13) Department of Medicine, Division of Hematology-Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (14) Department of Medicine, Division of Hematology-Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (15) Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (16) Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (17) Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (18) Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (19) Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (20) Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (21) Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (22) Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (23) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (24) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (25) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (26) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (27) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (28) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (29) Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (30) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (31) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (32) Department of Internal Medicine, Division of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: heather.mcarthur@utsouthwestern.edu. (33) Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address: simon.knott@cshs.org.