Identification of cycling regulatory T cell precursors as conductors of immune escape during breast carcinoma progression PMID: 41997138

ADC Targets in Oncology

2026-04-10

Identification of cycling regulatory T cell precursors as conductors of immune escape during breast carcinoma progression

Cancer Cell. 2026 Jun 8;44(6):1179-1200.e14. doi: 10.1016/j.ccell.2026.03.015.

Triet Minh Bui ¹ , Ernesto Rojas Jimenez ¹ , Zheqi Li ¹ , Pierre Foidart ¹ , Julieann Puleo ¹ , Pengze Yan ¹ , Aashna Jhaveri ² , Lin Yang ² , Jun Nishida ¹ , Marco Seehawer ¹ , Xinran Cai ¹ , Kimberly Ann Parker ¹ , Xiaodi Qin ³ , Oyku Ece Sumer ⁴ , Xiao-Yun Huang ⁴ , Ashka Patel ⁵ , Deborah Dillon ⁶ , Charles H McDonnell 3rd ⁷ , Ron Rowberry ⁷ , Shinedeep Jhajj ⁷ , Catherine Baker ⁷ , Daniel D Brown ⁸ , Siri H Strand ⁹ , Jeffrey R Marks ¹⁰ , Graham A Colditz ¹¹ , So Yeon Park ¹² , Adrian V Lee ¹³ , Michael Angelo ⁹ , Priscilla F McAuliffe ¹⁴ , Kristie Bobolis ⁷ , Robert West ⁹ , Glenn Dranoff ⁴ , E Shelley Hwang ¹⁰ , Simona Cristea ² , Kornelia Polyak ¹⁵

Affiliations

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 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.
3. Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27705, USA.
4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, 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.
6. Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
7. Sutter Institute for Medical Research, Roseville, CA 95661, USA.
8. Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.
9. Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
10. Department of Surgery, Duke University School of Medicine, Durham, NC 27708, USA.
11. Department of Surgery, Washington University School of Medicine, St. Louis, MO 63108, USA.
12. Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi, Republic of Korea.
13. Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA; UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.
14. UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.
15. 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: [email protected].

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 αOX40 and αPD-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.

Keywords

dendritic cells; ductal carcinoma in situ; immune escape; immuno-oncology; progenitor T cells; regulatory T cells; single-cell transcriptomic atlas.