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Identification of an immune-suppressed subtype of feline triple-negative basal-like invasive mammary carcinomas, spontaneous models of breast cancer

Elie Dagher 1 Laura Simbault 1 Jérôme Abadie 2, 1 Delphine Loussouarn 2, 3 Mario Campone 2, 4 Frédérique Nguyen 2, 1, 4, *
* Corresponding author
1 AMaROC - Animaux modèles pour la recherche en oncologie comparée
ONIRIS - Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique
2 CRCINA-ÉQUIPE 8 - Stress Adaptation and Tumor Escape in Breast Cancer
CRCINA - Centre de Recherche en Cancérologie et Immunologie Nantes-Angers
Abstract : Feline invasive mammary carcinomas are characterized by their high clinical aggressiveness, rare expression of hormone receptors, and pathological resemblance to human breast cancer, especially triple-negative breast cancer (negative to estrogen receptor, progesterone receptor, and epidermal growth factor receptor type 2). Recent gene expression studies of triple-negative breast cancers have highlighted their heterogeneity and the importance of immune responses in their biology and prognostic assessment. Indeed, regulatory T cells may play a crucial role in producing an immune-suppressed microenvironment, notably in triple-negative breast cancers. Feline invasive mammary carcinomas arise spontaneously in immune-competent animals, in which we hypothesized that the immune tumor microenvironment also plays a role. The aims of this study were to determine the quantity and prognostic value of forkhead box protein P3-positive peritumoral and intratumoral regulatory T cells in feline invasive mammary carcinomas, and to identify an immune-suppressed subgroup of triple-negative basal-like feline invasive mammary carcinomas. One hundred and eighty female cats with feline invasive mammary carcinomas, treated by surgery only, with 2-year follow-up post-mastectomy, were included in this study. Forkhead box protein P3, estrogen receptor, progesterone receptor, Ki-67, epidermal growth factor receptor type 2, and cytokeratin 14 expression were assessed by automated immunohistochemistry. Peritumoral regulatory T cells were over 300 times more abundant than intratumoral regulatory T cells in feline invasive mammary carcinomas. Peritumoral and intratumoral regulatory T cells were associated with shorter disease-free interval and overall survival in both triple-negative (ER-, PR-, HER2-, N = 123 out of 180) and luminal (ER+ and/or PR+, N = 57) feline invasive mammary carcinomas. In feline triple-negative basal-like (CK14+) mammary carcinomas, a regulatory T-cell-enriched subgroup was associated with significantly poorer disease-free interval, overall survival, and cancer-specific survival than regulatory T-cell-poor triple-negative basal-like feline invasive mammary carcinomas. High regulatory T-cell numbers had strong and negative prognostic value in feline invasive mammary carcinomas, especially in the triple-negative basal-like subgroup, which might contain a ''basal-like immune-suppressed'' subtype, as described in triple-negative breast cancer. Cats with feline invasive mammary carcinomas may thus be interesting spontaneous animal models to investigate new strategies of cancer immunotherapy in an immune-suppressed tumor microenvironment.
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Elie Dagher, Laura Simbault, Jérôme Abadie, Delphine Loussouarn, Mario Campone, et al.. Identification of an immune-suppressed subtype of feline triple-negative basal-like invasive mammary carcinomas, spontaneous models of breast cancer. Tumor Biology, Springer Verlag, 2020, 42 (1), pp.1010428319901052. ⟨10.1177/1010428319901052⟩. ⟨inserm-02484624⟩

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