Dagher Elie, Simbault Laura, Abadie Jérôme, Loussouarn Delphine, Campone Mario, Nguyen Frédérique
AMaROC, Oniris (Nantes Atlantic College of Veterinary Medicine, Food Science and Engineering), Nantes, France.
CRCINA, INSERM, Université d'Angers, Université de Nantes, Nantes, France.
Tumour Biol. 2020 Jan;42(1):1010428319901052. doi: 10.1177/1010428319901052.
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.
猫侵袭性乳腺癌的特点是临床侵袭性高、激素受体表达罕见，且在病理上与人类乳腺癌相似，尤其是三阴性乳腺癌（雌激素受体、孕激素受体和表皮生长因子受体2均为阴性）。最近对三阴性乳腺癌的基因表达研究突出了其异质性以及免疫反应在其生物学和预后评估中的重要性。事实上，调节性T细胞可能在产生免疫抑制微环境中起关键作用，尤其是在三阴性乳腺癌中。猫侵袭性乳腺癌在免疫健全的动物中自发产生，我们推测免疫肿瘤微环境在其中也发挥作用。本研究的目的是确定猫侵袭性乳腺癌中叉头框蛋白P3阳性的瘤周和瘤内调节性T细胞的数量及其预后价值，并识别三阴性基底样猫侵袭性乳腺癌的免疫抑制亚组。本研究纳入了180只仅接受手术治疗的患有猫侵袭性乳腺癌的雌性猫，术后进行了2年随访。通过自动免疫组织化学评估叉头框蛋白P3、雌激素受体、孕激素受体、Ki-67、表皮生长因子受体2和细胞角蛋白14的表达。在猫侵袭性乳腺癌中，瘤周调节性T细胞比瘤内调节性T细胞丰富300多倍。瘤周和瘤内调节性T细胞与三阴性（雌激素受体阴性、孕激素受体阴性、人表皮生长因子受体2阴性，180只中有123只）和管腔型（雌激素受体阳性和/或孕激素受体阳性，57只）猫侵袭性乳腺癌较短的无病生存期和总生存期相关。在猫三阴性基底样（细胞角蛋白14阳性）乳腺癌中，与调节性T细胞较少的三阴性基底样猫侵袭性乳腺癌相比，调节性T细胞富集的亚组的无病生存期、总生存期和癌症特异性生存期明显更差。调节性T细胞数量高在猫侵袭性乳腺癌中具有强烈的负面预后价值，尤其是在三阴性基底样亚组中，该亚组可能包含如三阴性乳腺癌中所述的“基底样免疫抑制”亚型。因此，患有猫侵袭性乳腺癌的猫可能是研究免疫抑制肿瘤微环境中癌症免疫治疗新策略的有趣的自发动物模型。
