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Cited by 16Effects of Radiation ExposureCancer Immunotherapy and BiomarkersImmune cells in cancer

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Aggressive Mammary Cancers Lacking Lymphocytic Infiltration Arise in Irradiated Mice and Can Be Prevented by Dietary Intervention

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Omene, Coral, Ma, Lin, Moore, Jade, Ouyang, Haoxu, Illa-Bochaca, Irineu, Chou, William, Patel, Manan S., Sebastiano, Christopher, Demaria, Sandra, Mao, Jian-Hua, Karagoz, Kubra, Gatza, Michael L., Barcellos-Hoff, Mary Helen·2020·Cancer Immunology Research
DOI 10.1158/2326-6066.cir-19-0253PMC PMC7002223

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Abstract

Because the incidence of breast cancer increases decades after ionizing radiation exposure, aging has been implicated in the evolution of the tumor microenvironment and tumor progression. Here, we investigated radiation-induced carcinogenesis using a model in which the mammary glands of 10-month-old BALB/c mice were transplanted with Trp53-null mammary tissue 3 days after exposure to low doses of sparsely ionizing γ-radiation or densely ionizing particle radiation. Mammary transplants in aged, irradiated hosts gave rise to significantly more tumors that grew more rapidly than those in sham-irradiated mice, with the most pronounced effects seen in mice irradiated with densely ionizing particle radiation. Tumor transcriptomes identified a characteristic immune signature of these aggressive cancers. Consistent with this, fast-growing tumors exhibited an immunosuppressive tumor microenvironment with few infiltrating lymphocytes, abundant immunosuppressive myeloid cells, and high COX-2 and TGFβ. Only irradiated hosts gave rise to tumors lacking cytotoxic CD8+ lymphocytes (defined here as immune desert), which also occurred in younger irradiated hosts. These data suggest that host irradiation may promote immunosuppression. To test this, young chimera mice were fed chow containing a honeybee-derived compound with anti-inflammatory and immunomodulatory properties, caffeic acid phenethyl ester (CAPE). CAPE prevented the detrimental effects of host irradiation on tumor growth rate, immune signature, and immunosuppression. These data indicated that low-dose radiation, particularly densely ionizing exposure of aged mice, promoted more aggressive cancers by suppressing antitumor immunity. Dietary intervention with a nontoxic immunomodulatory agent could prevent systemic effects of radiation that fuel carcinogenesis, supporting the potential of this strategy for cancer prevention.

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  • NTEs have been shown to impact initiation, promotion and progression stages of tumorigenesis at low doses of high LET radiation.

    “NTE have been shown to impact initiation, promotion and progression stages of tumorigenesis at low doses of high LET radiation (Illa-Bochaca et al., 2014;Omene et al., 2020;Maxwell et al., 2008;Kadhim et al., 2013;Lorimore et al., 2003;Barcellos-Hoff and Mao, 2016;Hada et al., 2014;Nagasawa and Little, 1992;Belyakov et al., 2005;Chang et al., 2016).”

    From A proposed change to astronaut exposures limits is a giant leap backwards for radiation protection (2021) · cites this paper as Omene et al., 2020

    The Discussion (page not provided) defines non-targeted effects as changes to cell signaling and the microenvironment, and distinguishes them from radiation-induced initiation. The Results report increased tumor frequency and faster growth after host irradiation, including densely ionizing radiation; the Methods describe doses of 30–80 cGy for that radiation. Thus the paper supports effects on promotion and progression, but not the claim that non-targeted effects impact initiation. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In mammary tumors, differences in tumor types comparing heavy ions to low LET radiation were observed, with more aggressive tumors observed.

    “Mammary tumors (Illa-Bochaca et al., 2014;Omene et al., 2020;Imaoka et al., 2007) Differences in mammary tumor types comparing heavy ions to low LET radiation with more aggressive tumors observed.”

    From A proposed change to astronaut exposures limits is a giant leap backwards for radiation protection (2021) · cites this paper as Omene et al., 2020

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Metadata

Authors
Omene, C., Ma, L., Moore, J., Ouyang, H., Illa-Bochaca, I., Chou, W., Patel, M. S., Sebastiano, C., Demaria, S., Mao, J.-H., Karagoz, K., Gatza, M. L., & Barcellos-Hoff, M. H.
Affiliations
  • Rutgers, The State University of New Jersey (US)
  • University of California, San Francisco (US)
  • New York University (US)
  • Lawrence Berkeley National Laboratory (US)
  • 1Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.
  • 2University of California, San Francisco, San Francisco, California.
ORCID
Venue
Cancer Immunology Research
Publisher
American Association for Cancer Research (AACR)
Published
2020-02-01
Volume
8
Issue
2
Pages
217-229
ISSN
  • 2326-6066 (ISSN-L)
  • 2326-6074
DOI
10.1158/2326-6066.cir-19-0253
PMC
PMC7002223
OpenAlex
W2995320262
Cited by
16
References
2
Citations by year
2026: 2 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 1
FWCI
1.49
Type
journal article
Language
en
Open access
Locations
  • Cancer Immunology Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
Funders
  • NASA (NNX09AM52G)
  • NIH (R01CA190980, R01CA19098005S1)
  • University of California, San Francisco (K08 CA172722)
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
radiation-induced cancer, breast cancer, immunosuppressive tumor microenvironment, lymphocyte infiltration, aging, particle radiation, gamma radiation, CD8+ T cells, myeloid cells, cyclooxygenase-2, TGF-beta, caffeic acid phenethyl ester, dietary intervention, cancer prevention, immunomodulators, honey bee products
MeSH terms
Age Factors, Animals, Diet, Dose-Response Relationship, Radiation, Female, Inflammation, Mammary Neoplasms, Experimental, Mice, Inbred BALB C, Neoplasms, Radiation-Induced, Tumor Suppressor Protein p53, Lymphocytes, Tumor-Infiltrating, Mice, Knockout, CD8-Positive T-Lymphocytes, Mice, Tumor Microenvironment, Transcriptome

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