Endostatin联合NK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, accumulating researches suggest that antiangiogenic therapy is not satisfactory for inhibiting tumor growth, and even has a risk of tumor recurrence and metastasis. This phenomenon is related to a series of changes happened in tumor microenvironment, especially recruiting a large number of immunosuppressive cells such as Treg cells, MDSCs and TAMs, and resulted in the immunosuppression states of tumor microenvironment. Our recent studies have found that the numbers of MDSCs and TAMs, including the amounts of their related cytokines, increased in the tumor microenvironment after Endostatin treatment, suggesting that the antiangiogenic therapy may increase the immunosuppressive state of tumor microenvironment, and the inhibition of NK cells. Based on our previous studies, we plan to study the changes of immunosuppressive state in tumor microenvironment increased by Endostatin, and the role of proliferating NK cells to kill tumor cells, and then develop the research of synergistic antitumor effects of Endostatin with NK cells adoptive immunotherapy on tumor growth. This makes pioneering scientific significance to demonstrate that the mechanisms of antiangiogenesis resistance; the inevitable link among the function of NK cells, the immunosuppression states of tumor microenvironment and the tumor metastasis. And this makes new perspective expanding on cancer therapy 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，不断积累的证据表明，抗血管生成疗效不理想，甚至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Treg、MDSC、TAM等免疫细胞募集导致肿瘤微环境免疫抑制状态。最近，我们的研究发现，Endostatin耐药进展的肿瘤微环境中MDSC、TAM及相关细胞因子增加。因此，我们推测，Endostatin也会加重肿瘤微环境免疫抑制状态，特别是NK细胞功能障碍。本研究旨在原有研究的基础上，拟开展Endostatin加重肿瘤微环境免疫抑制状态的研究，NK细胞克隆增殖杀伤肿瘤细胞的作用研究，进而开展Endostatin联合NK细胞过继免疫治疗协同抗肿瘤生长作用及机制研究。这对深入阐明抗肿瘤血管生长耐药机理，验证NK细胞功能与肿瘤微环境免疫抑制状态、肿瘤转移的关系，拓展肿瘤研究新思维具有开创性科学意义。

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，不断积累的证据表明，抗血管生成疗效不理想，甚至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，尤其是以MDSCs、TAM等免疫细胞募集导致肿瘤微环境免疫抑制状态。在本次研究中我们发现Endostatin在抑制肿瘤血管新生的同时，也会加重肿瘤微环境的缺氧，伴随着IL-4、IL-6、TGF-β、CCL2等细胞因子增多。Endostatin引起的这种微环境变化一方面易于趋化免疫抑制细胞如MDSCs、巨噬细胞至肿瘤微环境中，并诱导巨噬细胞的极性向M2样巨噬细胞转化；另一方面缺氧和TGF-β又能抑制免疫效应细胞如NK细胞的增殖和免疫效应，使得Endostatin治疗后肿瘤微环境中的免疫抑制状态加重，不利于该药抗肿瘤治疗的疗效。最后我们分离和培养了NK细胞，并将Endostatin和NK细胞过继免疫治疗相联合，观察到二者具有一定协同抗肿瘤生长的作用。本次研究的结果有助于进一步阐明抗肿瘤血管生长与肿瘤微环境免疫状态、肿瘤转移的关系，拓展了肿瘤抗血管治疗研究的新思维。