دورية أكاديمية
أعرض في EDS

Estrogen receptor blockade and radiation therapy cooperate to enhance the response of immunologically cold ER+ breast cancer to immunotherapy.

التفاصيل البيبلوغرافية
العنوان: Estrogen receptor blockade and radiation therapy cooperate to enhance the response of immunologically cold ER+ breast cancer to immunotherapy.
المؤلفون: O'Leary KA; Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, University of Wisconsin-Madison, Madison, WI, USA., Bates AM; Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin-Madison, Madison, WI, USA., Jin WJ; Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin-Madison, Madison, WI, USA., Burkel BM; Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin-Madison, Madison, WI, USA., Sriramaneni RN; Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin-Madison, Madison, WI, USA., Emma SE; Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin-Madison, Madison, WI, USA., Nystuen EJ; Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin-Madison, Madison, WI, USA., Sumiec EG; Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin-Madison, Madison, WI, USA., Ponik SM; Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin-Madison, Madison, WI, USA., Morris ZS; Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin-Madison, Madison, WI, USA. zmorris@humonc.wisc.edu.; University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA. zmorris@humonc.wisc.edu., Schuler LA; Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, University of Wisconsin-Madison, Madison, WI, USA. linda.schuler@wisc.edu.; University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA. linda.schuler@wisc.edu.
المصدر: Breast cancer research : BCR [Breast Cancer Res] 2023 Jun 13; Vol. 25 (1), pp. 68. Date of Electronic Publication: 2023 Jun 13.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: BioMed Central Ltd Country of Publication: England NLM ID: 100927353 Publication Model: Electronic Cited Medium: Internet ISSN: 1465-542X (Electronic) Linking ISSN: 14655411 NLM ISO Abbreviation: Breast Cancer Res Subsets: MEDLINE
أسماء مطبوعة: Publication: London, UK : BioMed Central Ltd
Original Publication: London, UK : Current Science, c1999-
مواضيع طبية MeSH: Receptors, Estrogen* , Neoplasms*, Animals ; Mice ; Fulvestrant/pharmacology ; Immunotherapy ; Estrogens ; Estrogen Antagonists ; Immunosuppressive Agents
مستخلص: Background: Most patients with estrogen receptor positive (ER+) breast cancer do not respond to immune checkpoint inhibition (ICI); the tumor microenvironment (TME) of these cancers is generally immunosuppressive and contains few tumor-infiltrating lymphocytes. Radiation therapy (RT) can increase tumor inflammation and infiltration by lymphocytes but does not improve responses to ICIs in these patients. This may result, in part, from additional effects of RT that suppress anti-tumor immunity, including increased tumor infiltration by myeloid-derived suppressor cells and regulatory T cells. We hypothesized that anti-estrogens, which are a standard of care for ER+ breast cancer, may ameliorate these detrimental effects of RT by reducing the recruitment/ activation of suppressive immune populations in the radiated TME, increasing anti-tumor immunity and responsiveness to ICIs.
Methods: To interrogate the effect of the selective estrogen receptor downregulator, fulvestrant, on the irradiated TME in the absence of confounding growth inhibition by fulvestrant on tumor cells, we used the TC11 murine model of anti-estrogen resistant ER+ breast cancer. Tumors were orthotopically transplanted into immunocompetent syngeneic mice. Once tumors were established, we initiated treatment with fulvestrant or vehicle, followed by external beam RT one week later. We examined the number and activity of tumor infiltrating immune cells using flow cytometry, microscopy, transcript levels, and cytokine profiles. We tested whether fulvestrant improved tumor response and animal survival when added to the combination of RT and ICI.
Results: Despite resistance of TC11 tumors to anti-estrogen therapy alone, fulvestrant slowed tumor regrowth following RT, and significantly altered multiple immune populations in the irradiated TME. Fulvestrant reduced the influx of Ly6C+Ly6G+ cells, increased markers of pro-inflammatory myeloid cells and activated T cells, and augmented the ratio of CD8+: FOXP3+ T cells. In contrast to the minimal effects of ICIs when co-treated with either fulvestrant or RT alone, combinatorial treatment with fulvestrant, RT and ICIs significantly reduced tumor growth and prolonged survival.
Conclusions: A combination of RT and fulvestrant can overcome the immunosuppressive TME in a preclinical model of ER+ breast cancer, enhancing the anti-tumor response and increasing the response to ICIs, even when growth of tumor cells is no longer estrogen sensitive.
(© 2023. The Author(s).)
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معلومات مُعتمدة: R01 CA179556 United States CA NCI NIH HHS; R01 CA206458 United States CA NCI NIH HHS; P30 CA014520 United States CA NCI NIH HHS; U01 CA233100 United States CA NCI NIH HHS; S10 OD023526 United States OD NIH HHS
فهرسة مساهمة: Keywords: Anti-estrogen; ER+ breast cancer; Fulvestrant; Immunotherapy; Radiation therapy
المشرفين على المادة: 0 (Receptors, Estrogen)
22X328QOC4 (Fulvestrant)
0 (Estrogens)
0 (Estrogen Antagonists)
0 (Immunosuppressive Agents)
تواريخ الأحداث: Date Created: 20230613 Date Completed: 20230615 Latest Revision: 20240510
رمز التحديث: 20240510
مُعرف محوري في PubMed: PMC10265911
DOI: 10.1186/s13058-023-01671-y
PMID: 37312163
قاعدة البيانات: MEDLINE
الوصف
تدمد:1465-542X
DOI:10.1186/s13058-023-01671-y