ICAM-1介导乳腺癌细胞对γδT细胞响应差异的分子机制

乳腺癌是威胁女性健康的重大疾病之一，人体γδT细胞疗法是乳腺癌治疗的新策略。申请人已发表工作表明，上调骨架微管蛋白的乙酰化修饰可增强γδT细胞的杀伤功能，并有效抑制三阴型乳腺癌细胞的转移。近期实验发现与γδT细胞共培养后，三阴型MDA-MB-231细胞和Luminal型MCF-7细胞的粘附分子ICAM-1及下游分子Rho A均不同程度下调，同时actin骨架被破坏并伴随细胞迁移能力的减弱；但HER2+型SkBr3细胞无以上变化。这些结果提示ICAM-1信号通路在调控不同分型乳腺癌细胞的迁移中具有重要作用。因此，我们的关键科学问题是，ICAM-1—RhoA—Actin轴如何介导不同分型乳腺癌细胞对γδT细胞的应答差异，其分子机制是什么？总之，本项目将揭示ICAM-1介导乳腺癌细胞对γδT细胞响应差异的分子机制，为选择γδT细胞治疗乳腺癌的适应症提供科学参考。

Breast cancer is one of the major threats to the health of women. γδ T cell-based immunotherapy has provided a new alternative treatment strategy. Nevertheless, the underlying mechanism of γδ T cell inhibiting breast cancer cell metastasis still needs to be further elucidated. Our published work indicated that the upregulation of tubulin acetylation could strengthen the cytotoxicity of γδ T cells and completely inhibit the metastasis of triple-negative cancer cells in mice. Our preliminary data showed that different types of human breast cancer cells response diversely to γδ T cell treatments. For example, in the presence of γδ T cells, both ICAM-1 and Rho A were down-regulated in triple-negative MDA-MB-231 cells and Luminal MCF-7 cells, and actin cytoskeleton was destructed as well. Such changes induced the reduction of cell migration of these two types of cell lines. However, HER2+ SkBr3 cells had no such alterations. These results indicated that ICAM-1 regulates cell migration diversely among different types of breast cancer cell lines. Therefore, our key scientific questions are: What are the response phenotypes of different types of breast cancer cells in the presence of γδ T cells? How does ICAM-1—RhoA—Actin axis regulate the different response phenotypes of different types of cancer cell lines to γδ T cells? In a word, this proposal will reveal the molecular mechanism determining the response to γδ T cells in different breast cancer molecular subtypes, thus providing scientific evidence for the application of γδ T cells in clinical settings.