BACKGROUND: Hormone receptor-positive (HR+) breast cancer responds poorly to immune checkpoint inhibitors (ICIs). In some settings, radiation therapy (RT) has been shown to mediate immunostimulatory effects and promote ICI sensitivity. METHODS: We investigated whether hypofractionated RT may be successfully combined with ICIs in a mouse model of multifocal, metachronous HR+ mammary carcinogenesis. We hypothesized that focal RT targeting the first detectable (primary) tumor combined with ICIs may generate effective immunity, delaying the development of new lesions. RESULTS: Focal RT in various doses and fractionations limited primary tumor growth, with an optimum for a 20-Gy × 2 regimen (ablative in approximately 90% of mice). The degree of primary disease control, however, did not necessarily correlate with overall survival extension because of changes in the development of new neoplastic lesions contributing to global tumor burden. Adding a PD-1 blocker to focal RT delivered in a 10-Gy × 3, 20-Gy × 2, or 8-Gy × 6 regimen failed to alter overall survival extension enabled by RT alone. Similar results were obtained with a CTLA4 blocker, an IL-1β inhibitor, and a PD-1 blocker plus recombinant FLT3LG when combined with the 10-Gy × 3 regimen. CONCLUSIONS: In this model of HR+ mammary carcinogenesis, RT to the primary tumor ameliorates overall survival (to an extent based on dose and fractionation). Increasing local control through RT alone or RT plus immunotherapy beyond a hitherto undefined threshold, however, does not necessarily inhibit the development of subsequent nonirradiated neoplasms and hence does not necessarily provide extra overall survival benefits.

Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadephia PA 19111 United States

Caryl and Israel Englander Institute for Precision Medicine New York NY 10065 United States

Department of Biochemistry and Molecular and Cell Biology University of Zaragoza Aragón Health Research Institute Zaragoza 50009 Spain

Department of Experimental and Clinical Medicine University of Florence Florence 50134 Italy

Department of Genetics Genomics and Informatics University of Tennessee Health Science Center Memphis TN 38163 United States

Department of Immunology Charles University 2nd Faculty of Medicine and University Hospital Motol Prague 150 06 Czech Republic

Department of Medicine Weill Cornell Medicine New York NY 10065 United States

Department of Pathology and Laboratory Medicine Weill Cornell Medicine New York NY 10065 United States

Department of Physiology and Biophysics Weill Cornell Medicine New York NY 10065 United States

Department of Population Health Sciences Weill Cornell Medicine New York NY 10065 United States

Department of Radiation Oncology Weill Cornell Medicine New York NY 10065 United States

Human Technopole Milan 20157 Italy

Institute for Computational Biomedicine Weill Cornell Medicine New York NY 10065 United States

Sandra and Edward Meyer Cancer Center New York NY 10065 United States

Sotio Prague 170 00 Czech Republic

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Giaquinto AN, Sung H, Miller KD, et al.Breast cancer statistics, 2022. CA Cancer J Clin. 2022;72:524-541. PubMed

Ponde NF, Zardavas D, Piccart M.. Progress in adjuvant systemic therapy for breast cancer. Nat Rev Clin Oncol. 2019;16:27-44. PubMed

Pan H, Gray R, Hayes DF; Early Breast Cancer Trialists’ Collaborative Group Breast-Cancer Recurrence after Stopping Endocrine Therapy. N Engl J Med. 2018;378:870-871. PubMed

Goel S, Bergholz JS, Zhao JJ.. Targeting CDK4 and CDK6 in cancer. Nat Rev Cancer. 2022;22:356-372. PubMed PMC

Petroni G, Buque A, Zitvogel L, et al.Immunomodulation by targeted anticancer agents. Cancer Cell. 2021;39:310-345. PubMed

Petroni G, Buque A, Coussens LM, et al.Targeting oncogene and non-oncogene addiction to inflame the tumour microenvironment. Nat Rev Drug Discov. 2022;21:440-462. PubMed

Petroni G, Formenti SC, Chen-Kiang S, et al.Immunomodulation by anticancer cell cycle inhibitors. Nat Rev Immunol. 2020;20:669-679. PubMed PMC

Im SA, Lu YS, Bardia A, et al.Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381:307-316. PubMed

Kroemer G, Chan TA, Eggermont AMM, et al.Immunosurveillance in clinical cancer management. CA Cancer J Clin. 2024;74:187-202. PubMed PMC

Cardoso F, McArthur HL, Schmid P, et al.LBA21 KEYNOTE-756: Phase III study of neoadjuvant pembrolizumab (pembro) or placebo (pbo) + chemotherapy (chemo), followed by adjuvant pembro or pbo + endocrine therapy (ET) for early-stage high-risk ER+/HER2– breast cancer. Annals of Oncology. 2023;34:S1260-S1261.

Rugo HS, Delord JP, Im SA, et al.Safety and antitumor activity of pembrolizumab in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Clin Cancer Res. 2018;24:2804-2811. PubMed

Emens LA. Breast cancer immunotherapy: facts and hopes. Clin Cancer Res. 2018;24:511-520. PubMed PMC

Galassi C, Chan TA, Vitale I, et al.The hallmarks of cancer immune evasion. Cancer Cell. 2024;42:1825-1863. PubMed

Bates JE, Sanders T, Arnone A, et al.Geographic density of linear accelerators and receipt of radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2021;111:e351-e352.

De Ruysscher D, Niedermann G, Burnet NG, et al.Radiotherapy toxicity. Nat Rev Dis Primers. 2019;5:13. PubMed

Galluzzi L, Aryankalayil MJ, Coleman CN, et al.Emerging evidence for adapting radiotherapy to immunotherapy. Nat Rev Clin Oncol. 2023;20:543-557. PubMed

Reits EA, Hodge JW, Herberts CA, et al.Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med. 2006;203:1259-1271. PubMed PMC

Newcomb EW, Demaria S, Lukyanov Y, et al.The combination of ionizing radiation and peripheral vaccination produces long-term survival of mice bearing established invasive GL261 gliomas. Clin Cancer Res. 2006;12:4730-4737. PubMed

Lhuillier C, Rudqvist NP, Yamazaki T, et al.Radiotherapy-exposed CD8+ and CD4+ neoantigens enhance tumor control. J Clin Invest. 2021;131: PubMed PMC

Golden EB, Formenti SC.. Is tumor (R)ejection by the immune system the "5th R" of radiobiology? Oncoimmunology. 2014;3:e28133. PubMed PMC

Zhou H, Tu C, Yang P, et al.Carbon ion radiotherapy triggers immunogenic cell death and sensitizes melanoma to anti-PD-1 therapy in mice. Oncoimmunology. 2022;11:2057892. PubMed PMC

Galluzzi L, Guilbaud E, Schmidt D, et al.Targeting immunogenic cell stress and death for cancer therapy. Nat Rev Drug Discov. 2024;23:445-460. PubMed PMC

Yamazaki T, Kirchmair A, Sato A, et al.Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy. Nat Immunol. 2020;21:1160-1171. PubMed

Sugita M, Yamazaki T, Alhomoud M, et al.Radiation therapy improves CAR T cell activity in acute lymphoblastic leukemia. Cell Death Dis. 2023;14:305. PubMed PMC

Gregucci F, Spada S, Barcellos-Hoff MH, et al.Updates on radiotherapy-immunotherapy combinations: Proceedings of 6th annual ImmunoRad conference. Oncoimmunology. 2023;12:2222560. PubMed PMC

Petroni G, Cantley LC, Santambrogio L, et al.Radiotherapy as a tool to elicit clinically actionable signalling pathways in cancer. Nat Rev Clin Oncol. 2022;19:114-131. PubMed PMC

Altorki NK, McGraw TE, Borczuk AC, et al.Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial. Lancet Oncol. 2021;22:824-835. PubMed

Leidner R, Crittenden M, Young K, et al.Neoadjuvant immunoradiotherapy results in high rate of complete pathological response and clinical to pathological downstaging in locally advanced head and neck squamous cell carcinoma. J Immunother Cancer. 2021;9:e002485. PubMed PMC

Buque A, Bloy N, Perez-Lanzon M, et al.Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer. Nat Commun. 2020;11:3819. PubMed PMC

Petroni G, Buque A, Yamazaki T, et al.Radiotherapy delivered before CDK4/6 inhibitors mediates superior therapeutic effects in ER(+) breast cancer. Clin Cancer Res. 2021;27:1855-1863. PubMed PMC

Buque A, Perez-Lanzon M, Petroni G, et al.MPA/DMBA-driven mammary carcinomas. Methods Cell Biol. 2021;163:1-19. PubMed

Williams MV, Denekamp J, Fowler JF.. A review of alpha/beta ratios for experimental tumors: Implications for clinical studies of altered fractionation. Int J Radiat Oncol Biol Phys. 1985;11:87-96. PubMed

Gu Z, Eils R, Schlesner M.. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics. 2016;32:2847-2849. PubMed

Wu T, Hu E, Xu S, et al.clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innovation (Camb). 2021;2:100141. PubMed PMC

Becht E, Giraldo NA, Lacroix L, et al.Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol. 2016;17:218. PubMed PMC

Vanpouille-Box C, Alard A, Aryankalayil MJ, et al.DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun. 2017;8:15618. PubMed PMC

Spears M, Talebian V, Liao L, et al.Abstract 2701: molecular profiling to assess the immune response to neoadjuvant SABR in early breast cancer. Cancer Res. 2021;81:2701-2701.

Zappasodi R, Serganova I, Cohen IJ, et al.CTLA-4 blockade drives loss of T(reg) stability in glycolysis-low tumours. Nature. 2021;591:652-658. PubMed PMC

Deng L, Liang H, Xu M, et al.STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014;41:843-852. PubMed PMC

Burnette BC, Liang H, Lee Y, et al.The efficacy of radiotherapy relies upon induction of type I interferon-dependent innate and adaptive immunity. Cancer Res. 2011;71:2488-2496. PubMed PMC

Maraskovsky E, Brasel K, Teepe M, et al.Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. J Exp Med. 1996;184:1953-1962. PubMed PMC

Lynch DH, Andreasen A, Maraskovsky E, et al.Flt3 ligand induces tumor regression and antitumor immune responses in vivo. Nat Med. 1997;3:625-631. PubMed

Vacchelli E, Vitale I, Eggermont A, et al.Trial watch: Dendritic cell-based interventions for cancer therapy. Oncoimmunology. 2013;2:e25771. PubMed PMC

Dinarello CA, Simon A, van der Meer JW.. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11:633-652. PubMed PMC

Hou Y, Yang K, Wang L, et al.Radiotherapy Enhances Metastasis Through Immune Suppression by Inducing PD-L1 and MDSC in Distal Sites. Clin Cancer Res. 2024;30:1945-1958. PubMed PMC

Jimenez-Cortegana C, Galassi C, Klapp V, et al.Myeloid-derived suppressor cells and radiotherapy. Cancer Immunol Res. 2022;10:545-557. PubMed

Jimenez-Cortegana C, Galluzzi L.. Myeloid-derived suppressor cells: emerging players in cancer and beyond. Int Rev Cell Mol Biol. 2023;375:xiii-xxix. PubMed

Demaria S, Ng B, Devitt ML, et al.Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys. 2004;58:862-870. PubMed