Endostatin联合γδT细胞过继免疫治疗协同抗肿瘤生长作用及机制研究

Antiangiogenic therapy has been thought to hold significant potential for the treatment of cancer. However,new researches suggest that antiangiogenic agents actually increase invasive and metastatic properties of cancer, and this refers to a series of changes happened in tumor microenvironment, especially cancer stem cells formation and the immunosuppression states of tumor microenvironment, this states results in the inhibition of activation and proliferation of γδT cells. We speculate that, Endostatin, as other antiangiogenic agents, would induce the changes happened in tumor microenvironment, and lead to the metastasis and recurrence of cancer. Based on our previous studies, we plan to carry out the study of Endostatin would induce a series of changes happened in tumor microenvironment, which impel the formation of cancer stem cells and immunosuppression states of tumor microenvironment niche, then check the efficient killing of cancer stem cells by γδT cells, and then develop the research of synergistic antitumor effects of Endostatin with γδT cells adoptive immunotherapy on tumor growth. This makes pioneering scientific significance to demonstrate that the mechanisms of tumor angiogenesis; the inevitable link between the changes of tumor microenvironment, cancer stem cells enrichment, and the inhibition of activation and proliferation of γδT cells; and the new perspective expanding on cancer therapy. And this has potential clinical application value as well.

抗血管生成曾被认为是最具希望的肿瘤治疗方法之一。然而，新近研究表明，抗血管生成不仅产生耐药，还会增加肿瘤转移复发风险，这涉及肿瘤微环境发生的一系列反应性变化，尤其是肿瘤干细胞形成及其局部免疫抑制状态，抑制了γδT细胞活化增殖。我们推测，正如其他肿瘤血管生成抑制剂一样，Endostatin也会诱导肿瘤微环境产生类似的改变，导致抗血管生成治疗耐药及肿瘤复发转移。本研究旨在原有研究的基础上，拟开展Endostatin引发肿瘤微环境发生促使肿瘤干细胞形成及肿瘤微环境免疫抑制状态研究，γδT细胞杀伤肿瘤干细胞的作用研究，进而开展Endostatin联合γδT细胞过继免疫治疗协同抗肿瘤生长及机制研究。这对进一步阐明肿瘤血管生长机理，验证肿瘤微环境变化与肿瘤干细胞生成，γδT细胞功能之间的必然联系，拓展肿瘤治疗新思维具有开创性科学意义，亦极具潜在临床应用价值。

抗血管生成治疗曾被认为是最具希望的肿瘤治疗方法之一，然而，最近的研究证据表明，抗血管生成治疗疗效有限，并且容易产生耐药现象。这涉及肿瘤微环境发生的一系列反应性变化，尤其是肿瘤干细胞样细胞增加及其局部免疫抑制状态有关。我们推测，正如其他肿瘤血管生成抑制剂一样，Endostatin也会诱导肿瘤微环境产生类似的改变，导致抗血管生成治疗耐药及肿瘤复发转移。本研究在原有研究的基础上，我们开展了Endostatin引发肿瘤微环境发生促使肿瘤干细胞形成及肿瘤微环境免疫抑制状态研究，γδT细胞杀伤肿瘤干细胞的作用研究，进而开展了Endostatin联合γδT细胞过继免疫治疗协同抗肿瘤生长及机制研究。我们建立了LLC荷瘤小鼠模型，用Aldefluor 实验从LLC荷瘤小鼠肿瘤组织中检测并分选ALDH+细胞群。我们发现Endostatin抗血管治疗后增加了ALDH+细胞生成，并且证明其具有干细胞样特性。进一步我们实验发现Endostatin治疗后可以加重肿瘤组织内部低氧以及促进TAM、MDSC和Treg细胞向肿瘤微环境中募集并可能通过分泌细胞因子如IL-6，EGF、TGF-β促进ALDH+生成。我们实验表明,Endostatin抗血管治疗通过加重肿瘤微环境缺氧及促进炎性细胞、免疫抑制细胞的招募使肺癌干细胞样细胞增多。从而提示，今后抗肿瘤血管治疗联合抗CSCs的治疗可能是一种提高抗肿瘤疗效的新策略。而在Endostatin治疗的血管正常化窗口期联合γδT细胞过继免疫治疗协同抗肿瘤也有一定研究潜力。