Using single-cell and spatial transcriptomics in human and rat models, Bui et al. mapped immune remodeling of normal breast, pre-malignant (DCIS) , and invasive (IBC) breast cancer and identified a proliferative FOXP3int MKI67hi cycling Treg (cycTreg) subset. CycTregs emerged at the DCIS-IBC junction, expanded in IBC, and predicted CD8+ infiltration, TCR diversity, disease-specific survival, and DCIS recurrence. CycTreg abundance correlated with CLEC10A+ cDC2s, high HLA class II, and IL-33-producing CAFs. OX40 agonism plus anti-PD-L1 or IL-33 blockade reduced cycTreg, remodeled CAF states, and restored antitumor immunosurveillance.
Contributed by Shishir Pant
ABSTRACT: Immune escape during the ductal carcinoma in situ (DCIS)-to-invasive breast cancer (IBC) transition shapes tumor evolution. Through transcriptomic mapping of the immune landscapes of normal breast, DCIS, and IBC from large patient cohorts, we identified T and myeloid cells as the primary distinguishing features between DCIS and IBC. We discovered cycling regulatory T cells (cycTreg) as an orchestrator of immunosuppression in IBC. cycTreg frequency predicts cytotoxic CD8(+), TCR diversity, disease-specific survival in IBC, and recurrence in DCIS. In a rat model of breast cancer, we demonstrated that cycTreg act as precursors to mature Treg and are inducible by tumor-localized type 2 dendritic cells. Profiling of tumors subjected to OX40 and PD-L1 therapies revealed an IL-33-mediated fibroblast-cycTreg signaling loop, the disruption of which enhances intratumoral antigen-experienced CD8(+) effectors and systemic immunosurveillance. Our study defines cycTreg as critical inducers of immune escape and promising immuno-oncology targets in breast cancer.
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (5) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (7) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. (8) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (11) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (12) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (13) Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27705, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (16) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. (17) Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. (18) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (19) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (20) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (21) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (22) Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA. (23) Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. (24) Department of Surgery, Duke University School of Medicine, Durham, NC 27708, USA. (25) Department of Surgery, Washington University School of Medicine, St. Louis, MO 63108, USA. (26) Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi, Republic of Korea. (27) Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA; UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA. (28) Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. (29) UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA. (30) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (31) Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. (32) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (33) Department of Surgery, Duke University School of Medicine, Durham, NC 27708, USA. (34) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. (35) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: kornelia_polyak@dfci.harvard.edu.
