The impact of breast radiotherapy on the tumor genome and immune ecosystem

Aislyn Schalck; Tuan Tran; Jianzhuo Li; Emi Sei; Shanshan Bai; Min Hu; Jerome Lin; Scott J Bright; Samuel Reddick; Fei Yang; Harsh Batra; Alejandro Contreras; Maria Gabriela Raso; Michael C Stauder; Karen E Hoffman; Jay P Reddy; Kevin T Nead; Benjamin D Smith; Gabriel O Sawakuchi; Wendy A Woodward; Stephanie S Watowich; Jennifer K Litton; Isabelle Bedrosian; Elizabeth A Mittendorf; Huong Le-Petross; Nicholas E Navin; Simona F Shaitelman

doi:10.1016/j.celrep.2025.115703

The impact of breast radiotherapy on the tumor genome and immune ecosystem

Cell Rep. 2025 May 27;44(5):115703. doi: 10.1016/j.celrep.2025.115703. Epub 2025 May 14.

Authors

Aislyn Schalck¹, Tuan Tran², Jianzhuo Li², Emi Sei², Shanshan Bai², Min Hu², Jerome Lin², Scott J Bright³, Samuel Reddick⁴, Fei Yang⁵, Harsh Batra⁶, Alejandro Contreras⁷, Maria Gabriela Raso⁶, Michael C Stauder⁸, Karen E Hoffman⁸, Jay P Reddy⁸, Kevin T Nead⁹, Benjamin D Smith⁸, Gabriel O Sawakuchi¹⁰, Wendy A Woodward⁸, Stephanie S Watowich¹¹, Jennifer K Litton¹², Isabelle Bedrosian¹³, Elizabeth A Mittendorf¹⁴, Huong Le-Petross¹⁵, Nicholas E Navin¹⁶, Simona F Shaitelman¹⁷

Affiliations

¹ Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biological Sciences, University of Texas, Houston, TX 770303, USA.
² Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Department of Breast Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
⁵ Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Janssen China Research & Development, Johnson&Johnson, Shanghai 201210, China.
⁶ Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Anatomical Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁸ Department of Breast Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁹ Department of Breast Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Graduate School of Biological Sciences, University of Texas, Houston, TX 770303, USA; Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹¹ Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹² Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹³ Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁴ Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA; Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
¹⁵ Department of Breast Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁶ Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biological Sciences, University of Texas, Houston, TX 770303, USA; Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: nnavin@mdanderson.org.
¹⁷ Department of Breast Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: sfshaitelman@mdanderson.org.

PMID: 40378044
DOI: 10.1016/j.celrep.2025.115703

Abstract

Radiotherapy is a pillar of breast cancer treatment; however, it remains unclear how radiotherapy modulates the tumor microenvironment. We investigated this question in a cohort of 20 patients with estrogen-receptor positive (ER⁺) breast tumors who received neoadjuvant radiotherapy. Tumor biopsies were collected before and 7 days postradiation. Single-cell DNA sequencing (scDNA-seq) and scRNA-seq were conducted on 8 and 11 patients, respectively, at these two time points. The scRNA data showed increased infiltration of naive-like CD4 T cells and an early, activated CD8 T cell population following radiotherapy. Radiotherapy also eliminated existing cytotoxic T cells and resulted in myeloid cell increases. In tumor cells, the scDNA-seq data showed a high genomic selection of subclones in half of the patients with high ER expression, while the remaining number had low genomic selection and an interferon response. Collectively, these data provide insight into the impact of radiotherapy in ER⁺ breast cancer patients.

Keywords: CP: Cancer; breast cancer; genomics; radiation; single cell; tumor microenvironment.

MeSH terms

Breast Neoplasms* / genetics
Breast Neoplasms* / immunology
Breast Neoplasms* / pathology
Breast Neoplasms* / radiotherapy
CD8-Positive T-Lymphocytes / immunology
Female
Genome, Human*
Humans
Middle Aged
Receptors, Estrogen / metabolism
Tumor Microenvironment* / genetics
Tumor Microenvironment* / immunology
Tumor Microenvironment* / radiation effects

Substances

Receptors, Estrogen