联合TLR7/8激动剂和Stat3抑制剂的抗肿瘤纳米疫苗增强肿瘤免疫疗法效果的研究

免疫系统的失调与恶性肿瘤的发生密切相关，抗原呈递细胞（包括巨噬细胞和树突状细胞）可捕获肿瘤碎片或人工合成的肿瘤抗原，通过抗原呈递激活肿瘤特异性T细胞，在肿瘤免疫疗法中有不可或缺的作用。然而，肿瘤会分泌IL-10等细胞因子，通过IL-10-Stat3信号轴抑制树突状细胞成熟，减少抗原呈递和共刺激信号。同时，抗原肽体内循环时间短且不易被抗原呈递细胞捕获，所以抗肿瘤疫苗并未得到充分的发展。本课题利用不饱和脂肪酸DHA修饰的TLR7/8激动剂和抗原肽包裹Stat3抑制剂，自组装成为多组分无载体一体化纳米肿瘤疫苗，以延长疫苗的体内循环时间，促进抗原呈递细胞吞噬抗原肽，并在多种肿瘤模型中研究新型纳米肿瘤疫苗是否可以通过激活TLR7/8-NFKB和抑制IL10-Stat信号轴促进树突状细胞成熟、交叉呈递抗原肽、激活肿瘤特异性T细胞，改变肿瘤微环境，增强PD-1单抗介导的肿瘤免疫疗法。

Malignant tumor is highly associated with the dysregulation of immune system, and immunotherapy can re-program the immune system to eliminate cancer cells by reversing the suppressive effects of cancer cells on T cells. Antigen-presenting cells, including macrophage and dendritic cells, play a key role in this process by presenting antigens to activate tumor-specific T cells after engulfing tumor cell debris as well as artificial tumor-specific antigens. However, tumor can suppress the maturation of dendritic cells via IL-10-Stat3 axis by secreting cytokines such as IL-10. Moreover, artificial tumor-specific antigens typically show a relatively short circulation time and low intake rates by antigen-presenting cells. Therefore, much should be done to improve antigen-based anti-tumor vaccine. This project aim to construct a self-assembling multi-component nano anti-tumor vaccine with a longer circulation time and a better cellular uptake by utilizing DHA-conjucated antigen and TLR7/8 agonist to encapsulate Stat3 inhibitor, and to evaluate its efficacy of promoting the maturation and antigen cross presentation of dendritic cells to activate tumor-specific T cells and improve the therapeutic effects of immunotherapy mediated by PD-1 antibody by modulating intratumor microenvironment.