肿瘤相关胞外抗原IGFBP-2诱导免疫抑制及机制研究

Tumor evolves the ability to induce antitumor immunosuppression via various mechanisms, which is the pre-requisite for carcinogenesis and metastasis. Regulatory T (Treg) cells play an important role in the maintenance of immunological self-tolerance by suppressing host immune responses against tumor. Little is known, however, about the nature of the physiological target antigens for CD4+ Treg cells. Previous studies demonstrated that some MHC class II-restricted tumor antigens induced the formation of CD4+Treg-like cells, which functionally suppressed the proliferation and IL-2 secretion of CD4+ effector T cells. Tumor cells with typical EMT features were reported to induce CD4+ Treg and impaired dendritic cells, and result in immunosuppression and accelerate cancer metastasis. We and other groups previously showed that IGFBP-2 was overexpressed in various tumor types and promoted tumor cell migration and invasion. IGFBP-2 has been recently reported to be a tumor-associated antigen with MHC class II epitopes. Our preliminary data indicate that IGFBP-2-overexpressing colon cancer cells exhibit EMT phenotypes and seemingly increase CD4+Foxp3+ T cells and enhance their resistance to killing by immune cells, altogether suggesting the potential of IGFBP-2 to induce antitumor immunosuppression. This project will adopt human and murine colon tumors as the study models, and in vitro and in vivo investigate whether IGFBP-2 could act as a tumor antigen and /or function through an EMT-mediated mechanism to induce immunosuppression and thus accelerate cancer metastasis. The supporting findings of the study will provide with experimental evidences for IGFBP-2 as a multifunctional therapeutic target for cancer therapy.

肿瘤通过多种机制诱导免疫抑制，是肿瘤发生和转移的前提。调节T细胞（Treg）抑制对肿瘤的免疫应答，在维持肿瘤免疫自身耐受中发挥重要作用。然而，对诱导和激活CD4+Treg细胞的生理靶抗原知之甚少。研究发现，肿瘤产生的MHC II类自身抗原诱导产生类似CD4+Treg细胞，其抑制CD4+T效应细胞增殖和活性；具有EMT特征的肿瘤细胞能诱导CD4+Treg和不成熟树突状细胞，产生免疫抑制，加速肿瘤转移。我们和其它团队研究发现，多种恶性肿瘤产生和分泌高浓度IGFBP-2，促进肿瘤细胞迁移和侵袭；IGFBP-2是MHC II肿瘤抗原，激活CD4+T细胞，增强结肠癌细胞抵抗免疫杀伤。因此，可能还具有诱导免疫抑制的功能。本项目以结肠肿瘤为模板，采用体外和体内实验手段，阐明IGFBP-2是否作为肿瘤抗原和/或通过EMT机制诱导免疫抑制，促进肿瘤转移,为研发IGFBP-2多功能药靶提供实验证据。

尽管不断改进手术、放疗和化疗的治疗方案，但对最恶性的脑肿瘤，胶质母细胞瘤(glioblastoma,GBM），的治疗疗效甚微，病人总生存期在15个月内。近年出现的肿瘤免疫治疗在其它肿瘤的良好治疗效果，如：黑色素瘤，给攻克GBM 带来希望。但针对GBM的免疫治疗靶点屈指可数，寻找合适的GBM 药靶成为迫切问题。. 本项目研究发现，IGFBP2 (Insulin-like growth factor binding protein 2)是治疗GBM患者的重要靶点，揭示了IGFBP2促进免疫抑制的细胞和分子机制；采用拮抗IGFBP2的单克隆抗体处理携带脑胶质瘤的小鼠，有效地解除小鼠机体和肿瘤微环境的免疫抑制状态，激活了抗肿瘤细胞的免疫反应，延长小鼠生存期 （约20%的小鼠的肿瘤完全消失）。在临床，IGFBP2 在≥ 60% GBMs肿瘤中过表达，患者血中升高的IGFBP2蛋白浓度直接与患者预后差、肿瘤复发相关。加上本项目的这些发现进一步支持IGFBP2是攻克GBM的目标靶点。目前，治疗GBM患者的靶药极少，我们未来的目标是把IGFBP2单抗药物向临床转化，为GBM患者提供一个新的潜在靶药。具体实验数据请见研究工作总结部分。. 该研究的意义及价值在于，首次在国际上提出分泌性癌相关抗原具有诱导免疫抑制的作用，对其抑制作用的机制的阐明提示这类分泌性癌相关抗原促进的免疫抑制作用具有很大的影响力，在小鼠模型观察到的解除抑制产生的明显抗癌效果，提示是一类极有前途的抗癌新药研发对象。我们将在今年开始做临床转化前的研究。如：开始进一步优化用药方案，在其它种属动物，如：狗，猴，进行药物毒副作用试验，以获取药物安全性数据等。