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

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

Free article

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

Aislyn Schalck et al. Cell Rep. 2025.

Free article

. 2025 May 27;44(5):115703.

doi: 10.1016/j.celrep.2025.115703. Epub 2025 May 14.

Authors

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.

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Conflict of interest statement

Declaration of interests B.D.S. reports royalty and equity interest in Oncora Medical and salary support from Varian Medical Systems. S.J.B. and G.O.S. have received research support from Alpha Tau and Artios. S.F.S. has a leadership role in the National Cancer Institute (NCI) BOLD Task Force; has received research support from Emerson Collective Foundation, Alpha Tau, and Artios; has contracted research support from Artidis and Exact Sciences; and has served as a consultant for Lumicell and BD. W.A.W. has grant support from the State of Texas, Susan G. Komen for the Cure Foundation, US Department of Defense, and NIH/NCI; serves on the advisory board of Exact Science; and has a leadership role as the ASTRO Science Steering Committee Chair. J.K.L. has grant or research support from Novartis, Medivation/Pfizer, Genentech, GSK, EMD-Serono, AstraZeneca, Medimmune, Zenith, and Merck; serves on the Speaker’s Bureau for MedLearning, Physician’s Education Resource, Prime Oncology, Medscape, Clinical Care Options, and Medpage; and receives royalties from UpToDate. E.A.M. reports compensated service on scientific advisory boards for AstraZeneca, Exact Sciences, Merck, and Roche/Genentech; uncompensated service on steering committees for Bristol Myers Squibb, Lilly, and Roche/Genentech; institutional research support from Roche/Genentech (via SU2C grant) and Gilead; and reports the following nonfinancial interests, nonremunerated activities: Board of Directors for the American Society of Clinical Oncology and Scientific Advisor for the Susan G. Komen for the Cure Foundation. K.E.H. reports research funding from the Rising Tide Foundation, Janssen, and Varian Medical Systems.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

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LinkOut - more resources

Full Text Sources

Medical

Research Materials

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