体内激活树突状细胞联合免疫抑制对结肠癌或肺癌模型的免疫治疗及机制研究

免疫疗法已成为继手术、化疗、放疗等疗法后最有望治愈癌症的方法。树突状细胞（Dendritic cells, DC）能有效递呈抗原，诱导Th1反应，发挥抗肿瘤作用。DC疫苗已成为肿瘤免疫治疗中最重要的力量之一，已有大量临床试验证实了其安全性和有效性。但DC体外荷载抗原难度大,疗效不确定，体内活化DC存在不同亚型和成熟状态的DC，能诱导免疫反应，也能诱导免疫耐受，影响疗效。因此，DC疫苗虽安全有效但仍须改进。探寻更有效的体内活化DC的方法，联合应用免疫抑制，有望获得更好的疗效。我们前期研究发现，HMGN1和R848可协同刺激DC，强化Th1反应, 抗TNFR2抗体能抑制调节性T细胞。因此提出假说：联合HMGN1、R848与抗TNFR2，能协同活化DC，诱导Th1反应，抑制免疫耐受，有望获得更好的疗效。本课题拟采用肿瘤细胞株与小鼠建立结肠癌、肺癌模型, 利用体内外试验，验证疗效并研究其机制。

Immunotherapies have emerged to become effective cancer treatments for use alongside surgical removal, radiation, chemotherapy and other targeted therapies. Dendritic cells (DC) are the most potent antigen presenting cells of the immune system capable of inducing an anti-tumor Th1 response. The DC vaccine has became one of the most powerful immunotherapies and has been proven to be feasible and safe in multiple clinical trials. However, the optimal approach for antigen loading to produce the strongest CTL response has yet to be identified. Another concern is that different DC subsets and immature DCs could induce immunosuppression. Therefore, The DC vaccine still needs to be improved. DC-based immunotherapy may have limitations as a monotherapy because of the immunosuppressive mechanism active in the tumor microenvironment. Whereas combination therapy may have better effects for the initiation of the DC vaccination and boost the antigen-specific anti-tumor immunity by subsequent treatment with immunosuppressing agents. While the potential impact of such regimen is recognized, an optimal combination treatment has yet to be be established. Our previous findings suggested that HMGN1 and R848 have synergistic effects on inducing and strengthening Th1 response, and anti-TNFR2 treatment can inhibit Treg. Therefore, we hypothesized that combining HMGN1and R848 with anti-TNFR2 or other immunosuppressing agents could induce stronger anti-tumor responses. In order to study whether the combination has better anti-tumor effects and its underlying mechanisms, colon cancer and lung cancer cell lines will be investigated in vitro and in vivo.