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

Journal Article · Thu Dec 12 00:00:00 EST 2019 · Cancer Immunology Research

DOI:https://doi.org/10.1158/2326-6066.cir-19-0253· OSTI ID:1637308

Omene, Coral ^[1]; Ma, Lin ^[2]; Moore, Jade ^[2]; Ouyang, Haoxu ^[3]; Illa-Bochaca, Irineu ^[3]; Chou, William ^[2]; Patel, Manan S. ^[3]; Sebastiano, Christopher ^[3]; Demaria, Sandra ^[3]; Mao, Jian-Hua ^[4]; Karagoz, Kubra ^[1]; Gatza, Michael L. ^[1]; Barcellos-Hoff, Mary Helen ^[2]

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1. Rutgers Univ., New Brunswick, NJ (United States)
2. Univ. of California, San Francisco, CA (United States)
3. New York Univ. (NYU), NY (United States)
4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

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. In this paper, 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.

• Research Organization: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
• Sponsoring Organization: National Aeronautic and Space Administration (NASA); National Institutes of Health (NIH); USDOE Office of Science (SC)
• Grant/Contract Number: AC02-05CH11231
• OSTI ID: 1637308
• Journal Information: Cancer Immunology Research, Journal Name: Cancer Immunology Research Journal Issue: 2 Vol. 8; ISSN 2326-6066
• Publisher: American Association for Cancer Research (AACR)
• Country of Publication: United States
• Language: English

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60 APPLIED LIFE SCIENCES