Shiao et al. profiled longitudinal biopsies from patients with TNBC using scRNAseq and multiplex IHC with spatial analysis (CODEX) to elucidate the immune response to PD-1 therapy in combination with radiotherapy (RT). Two responder (R1 and R2) and one non-responder (NR) patterns were identified. R1 exhibited high immune infiltrates at baseline and a vigorous T cell response after pembrolizumab. R2 had low immune infiltrates (similar to NR) at baseline, but showed delayed response after pembrolizumab and RT, similar to an orthotopic E0771 murine model of TNBC. NR showed low MHC class I/II expression at baseline and didn’t respond despite treatment.
Contributed by Shishir Pant
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.
