纳米疫苗通过激活天然免疫提高PD1抗体抗肿瘤疗效的机制和应用研究

免疫监测点阻断抗体如anti-PD1在多种肿瘤的治疗上取得了突破，然而其有效率仍然较低。如何提升anti-PD1的适用范围和疗效是肿瘤免疫治疗亟待解决的问题。我们的前期研究表明，一种包含天然免疫激动剂的纳米肿瘤疫苗能够激活抗原递呈细胞，提高肿瘤T细胞浸润和抗肿瘤效果。高效的抗原递呈和活化的免疫微环境是产生抗肿瘤T细胞的前期关键步骤，而anti-PD1能够解除抗肿瘤免疫反应后期PD1通路对T细胞的抑制。因此，我们预计纳米疫苗结合anti-PD1能扩大anti-PD1治疗的适用范围和提高疗效。 我们计划首先测试纳米疫苗对不敏感小鼠肿瘤的微环境的影响，然后明确纳米疫苗联合anti-PD1在不敏感小鼠肿瘤模型上的治疗效果；最后，我们将探索这种联合治疗的细胞和分子生物学机制。 本项目有望揭示肿瘤抵抗anti-PD1治疗的新机制，为设计新型组合免疫治疗扩大受益群体和提高疗效提供前期理论和实验依据。

Immune checkpoint blockade antibodies such as anti-PD1 have revolutionized the therapeutic landscape in treating multiple types of cancers. However, the response rate and anti-tumor efficacy was still limited. How to expand the applicable population and improve the therapy efficacy is a critical problem for cancer immunotherapy. Our preliminary findings showed that a nanovaccine including innate immune agonists could activate antigen presenting cells, improve tumor immune infiltration, and potentiate antitumor immunity. Efficient antigen presentation and an immune-active microenvironment is a prerequisite for fully functional antitumor T cells, while anti-PD1 release the brake for T cells from co-inhibitory signals. Thus, we hypothesize that nanovaccine in combination with anti-PD1 would greatly improve the applicable population and therapy efficacy. To test this hypothesis, we plan to 1. Determine the effect of nanovaccine on tumor microenvironment of immune-resistant cancers; 2. Determine the antitumor efficacy of nanovaccine in combination of anti-PD1; 3. Explore the molecular and cellular mechanisms by which the combination therapy potentiate antitumor immunity. Our research may identify new mechanism by which some tumors resist anti-PD1 therapy, and provide preclinical evidence for developing new therapeutic means to improve cancer immunotherapy.