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。

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.