微波消融治疗乳腺癌原发灶诱导NK细胞抑制远处转移灶的机制研究

Metastatic breast cancer is an incurable disease, and locoregional surgery of primary cancer can induce progression of metastatic tumors in liver and lung. However, locoregional surgery is essential for control of fungation and bleeding, and the improvement of quality of life. Therefore, effective locoregional treatment is urgent needed for metastatic breast cancer. Our experimental study and clinical trial have found that microwave ablation (MWA) is effective and safe for the treatment of breast cancer. Moreover, we have found MWA induces weak specific antitumor immunity in a murine model of breast cancer. MWA is a promising local treatment in the future. .Interestingly, we have found that local MWA of primary breast cancer mediates tumor regression in the lung in a murine model. Furthermore, tumor regression in the lung is associated with the number of NK cells. So, we confer that MWA of primary breast cancer induces NK cell response and mediates distal tumor regression. In the present study, we aim to determine the detailed NK cell response induced by MWA of primary breast cancer, which suppresses distal metastatic tumors. The underlying mechanisms will also be determined.

Ⅳ期乳腺癌是目前治疗的难点，外科手术切除原发灶会促进伴有肝/肺转移乳癌患者疾病的进展。而原发灶的处理对于控制局部症状、改善生活质量具有重要意义。寻找有效的局部治疗手段非常重要。课题组经过系列研究证实微波消融（MWA）治疗乳腺癌的可行性，并阐明MWA治疗乳腺癌可引起一定的免疫效应。MWA有望成为乳腺癌局部治疗的重要手段。课题组发现MWA治疗小鼠乳腺癌原发灶，其肺转移灶受到抑制；并发现这一现象主要与NK细胞相关的重要证据。因此MWA治疗乳腺癌原发灶可能通过诱导NK细胞发挥抑制远处转移灶的作用。本课题拟系统探讨MWA治疗乳腺癌原发灶后转移灶局部微环境和全身的免疫学特征；明确MWA是否依赖NK细胞增强系统性抗肿瘤免疫；筛选出起主要作用的细胞因子并探讨其机制；临床上验证MWA治疗乳腺癌激活NK细胞介导的抗肿瘤效应。希望通过本研究的开展，为Ⅳ期乳癌（尤其是伴有肝肺转移）的局部治疗提供一条全新的思路。

前期研究证实微波消融(MWA)治疗乳腺癌是安全、可行的，并发现MWA治疗可引起一定的免疫效应。我们发现MWA治疗小鼠乳腺癌原发灶后其远处肺转移受到抑制与小鼠的NK细胞免疫增强相关。由此，我们通过一系列体内外实验探讨MWA治疗乳腺癌调控NK细胞的机制，并深入验证MWA治疗乳腺癌原发灶抑制远处肺转移进展和NK细胞免疫之间的关系。研究发现MWA治疗乳腺癌原发灶诱导原发灶内巨噬细胞浸润增多；增多的巨噬细胞可以分泌大量IL-15进入循环；血浆中高浓度的IL-15是诱导外周NK细胞免疫增强的重要原因。在临床上，我们发现MWA治疗乳腺癌患者不仅可以诱导患者外周NK细胞免疫效应增强，还可以通过激活外周CD4+T细胞的ICOS通路诱导Th1型抗肿瘤免疫效应增强。考虑到消融治疗乳腺癌的局部治疗效果安全可靠，并且可以激起一定强度的抗肿瘤免疫反应。相较于传统手术治疗，消融与免疫治疗联合可能是一种全新的治疗理念和策略，值得进一步深入探索。