仿生纳米囊调控髓系来源抑制细胞用于增强肿瘤免疫治疗的应用及机制研究

The reversal of the immunosuppressive effect mediated by myeloid-derived suppressor cells (MDSCs) residing in tumor microenvironment has drawn great attentions. Although antibodies, small molecule inhibitors, and chemotherapeutic drugs have been proven effective in the regulation of MDSCs, they have obvious drawbacks. Therefore, it is urgent to develop effective strategies for regulating MDSCs. Based on our previous studies, this project will focus on the key scientific issues of how to inhibit the generation, recruitment and function of MDSCs using biomimetic nanovesicles, and thus to reverse the of tumor immunosuppressive microenvironment and to improve therapeutic outcomes of immunotherapy. We will to prepare neutrophil-mimicking “cytokine nanosponge”, which can adsorb cytokines that are involved in the recruitment and activation of MDSCs. These nanovesicles are expected to reduce the production of granulocytes and monocytes in bone marrow and spleen, and block their homing at the tumor sites. The nanovesicles can inhibit the immunosuppressive effect mediated by MDSCs in tumor microenvironment and improve the immune response of anti-tumor immune cells, thereby improve the therapeutic effect. Furthermore, we will also study the immunosuppressive mechanisms of MDSCs and the anti-tumor mechanism of the biomimetic nanovesicles. This project will provide guidance for future research and application of tumor immunotherapy by intervening immunosuppressive cell infiltration.

如何削弱肿瘤微环境中髓系来源抑制细胞（MDSCs）的免疫抑制作用，增强抗肿瘤免疫应答是肿瘤治疗领域的热点和难点。尽管已有抗体、小分子抑制剂及化疗药物等手段在MDSCs的调控方面效果明显，但各有其显著缺陷，亟待发展调控MDSCs的有效手段和新策略。本项目基于前期研究基础，拟围绕“如何通过仿生纳米囊抑制MDSCs产生、募集和功能，从而改善肿瘤免疫抑制微环境，提高免疫治疗效果”的关键科学问题展开；合成仿生中性粒细胞膜的“细胞因子纳米海绵”，吸附MDSCs募集及功能活化相关的细胞因子；减少粒细胞和单核细胞在骨髓和脾脏中的产生，阻断其在肿瘤部位的富集；抑制其在肿瘤微环境中的免疫抑制作用，提高抗肿瘤免疫细胞的免疫应答，增强肿瘤治疗效果；进一步阐明MDSCs的免疫抑制机制及仿生纳米囊的抗肿瘤相关机理。本项目研究将为干预免疫抑制细胞浸润用于肿瘤治疗的研究和应用提供理论支持和指导。

放疗是传统的肿瘤治疗手段之一。然而，肿瘤特殊的微环境对放疗疗效产生了较大的影响。缺氧是肿瘤微环境的关键特征之一，由于DNA损伤维持所需的供氧不足而导致放疗抵抗。此外，肿瘤深部组织中血管的组织和形态异常，以及致密的细胞外基质对放射增敏剂渗透富集以及氧气随血液灌注至肿瘤病灶内部造成一定阻碍。因此，本课题在国家自然科学基金资助下开发出一种对肿瘤微环境具有高度胞吞转运潜能的转胞运“纳米石榴”（Hybrid Transcytosis Nanopomegranates，HTP）。该HTP的构建基于正常生理条件下的小粒径CuS和Au纳米颗粒（Nanoparticles,NPs）的自组装。HTP可在具有阳离子化表面的肿瘤酸性微环境中快速解离为具有胞吞转运作用的NPs（CuS和Au NPs），这一特性有助于发挥其转胞运潜能，并有效增强CuS-NPs和Au-NPs向深部肿瘤组织的渗透能力。经近红外二区（NIR(II)）激光照射后，CuS-NPs“加热”肿瘤细胞，升温效果直接杀伤肿瘤细胞，并增强肿瘤病灶血液灌注，进而促进肿瘤缺氧缓解和DNA损伤加重。此外，血管扩张后在深部肿瘤组织中进一步富集的Au-NPs可更加有效地发挥放疗增敏作用。综上所述，本研究为改善肿瘤缺氧并提升深部肿瘤组织放疗增敏作用提供了一个颇具潜能的新型纳米平台。