CD4 T-cell immune stimulation of HER2 + breast cancer cells alters response to trastuzumab in vitro.
CD4 T-cell immune stimulation of HER2 + breast cancer cells alters response to trastuzumab in vitro.
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DOI：
10.1186/s12935-020-01625-w
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发表时间：
2020-11-10
影响因子：
5.8
通讯作者：
Sorace AG
中科院分区：
文献类型：
--
作者：
Song PN;Mansur A;Dugger KJ;Davis TR;Howard G;Yankeelov TE;Sorace AG
HER2 +肿瘤免疫微环境由巨噬细胞、自然杀伤细胞和肿瘤浸润淋巴细胞组成，产生促炎细胞因子。在治疗期间确定t细胞对HER2 +癌细胞的作用可以指导触发抗体依赖性细胞毒性的免疫原性治疗。本研究利用体外纵向时间分辨显微镜测量t细胞对HER2阳性乳腺癌曲妥珠单抗的影响。将荧光标记的乳腺癌细胞（BT474、SKBR3、MDA-MB-453和MDA-MB-231）与CD4 + t细胞（Jurkat细胞系）共培养，并纵向成像以量化使用或不使用曲妥珠单抗（10、25、50和100 μg/mL）时的癌细胞活力。操纵t细胞共培养的存在和时间，以确定曲妥珠单抗治疗的HER2 +乳腺癌的免疫刺激。分别用western blot和ELISA法检测HER2和TNF-α的表达。采用双尾参数t检验计算显著性。当暴露于25 μg/mL曲妥珠单抗和t细胞时，HER2 +癌细胞的活力与暴露于曲妥珠单抗而不含t细胞的癌细胞相比显著降低（p = 0.01）。t细胞的存在显著增加了曲妥珠单抗治疗的癌细胞中TNF-α的表达（p = 0.02）。相反，用TNF-α和曲妥珠单抗治疗的癌细胞与曲妥珠单抗治疗的癌细胞与t细胞共培养的癌细胞具有相似的活力下降（p = 0.32）。t细胞的存在显著提高了靶向治疗的疗效，表明曲妥珠单抗可能引发免疫介导的细胞毒性。升高的TNF-α受体表达表明细胞因子可能与曲妥珠单抗相互作用，在HER2 +乳腺癌中产生对治疗的增强反应状态，这有可能减轻肿瘤负担。
The HER2 + tumor immune microenvironment is composed of macrophages, natural killer cells, and tumor infiltrating lymphocytes, which produce pro-inflammatory cytokines. Determining the effect of T-cells on HER2 + cancer cells during therapy could guide immunogenic therapies that trigger antibody-dependent cellular cytotoxicity. This study utilized longitudinal in vitro time-resolved microscopy to measure T-cell influence on trastuzumab in HER2 + breast cancer. Fluorescently-labeled breast cancer cells (BT474, SKBR3, MDA-MB-453, and MDA-MB-231) were co-cultured with CD4 + T-cells (Jurkat cell line) and longitudinally imaged to quantify cancer cell viability when treated with or without trastuzumab (10, 25, 50 and 100 μg/mL). The presence and timing of T-cell co-culturing was manipulated to determine immune stimulation of trastuzumab-treated HER2 + breast cancer. HER2 and TNF-α expression were evaluated with western blot and ELISA, respectively. Significance was calculated using a two-tailed parametric t-test. The viability of HER2 + cancer cells significantly decreased when exposed to 25 μg/mL trastuzumab and T-cells, compared to cancer cells exposed to trastuzumab without T-cells (p = 0.01). The presence of T-cells significantly increased TNF-α expression in trastuzumab-treated cancer cells (p = 0.02). Conversely, cancer cells treated with TNF-α and trastuzumab had a similar decrease in viability as trastuzumab-treated cancer cells co-cultured with T-cells (p = 0.32). The presence of T-cells significantly increases the efficacy of targeted therapies and suggests trastuzumab may trigger immune mediated cytotoxicity. Increased TNF-α receptor expression suggest cytokines may interact with trastuzumab to create a state of enhanced response to therapy in HER2 + breast cancer, which has potential to reducing tumor burden.
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影响因子：
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作者：
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DOI：
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发表时间：
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期刊：
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影响因子：
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