具有全身活性的新型天然免疫激动剂联合PD-1抑制剂的抗肿瘤疗效与作用机制研究

PD-1抑制剂为代表的肿瘤免疫治疗多集中于增强T细胞反应，但天然免疫活化是抗肿瘤T细胞启动的上游关键事件，寻求有效的天然免疫激活成为新一代免疫治疗的发展趋势。目前天然免疫激动剂主要为瘤内注射的局部给药方式，既导致了应用瘤种的局限性，也不利于远端转移病灶的控制，探索具有全身活性的天然免疫激动剂具有较好的科学性和迫切的临床需求。本团队与合作实验室前期证实锰可有效激活STING信号促进抗感染天然免疫，也可抑制小鼠肿瘤的生长；并率先注册了锰联合PD-1抑制剂全身给药方案的国际临床试验，在晚期转移性实体瘤中显示了良好的安全性和临床疗效。基于此，本课题拟从分子、细胞、组织和动物模型层面，利用单细胞测序等技术，系统解析锰激活全身天然免疫进而介导抗肿瘤获得性免疫的细胞与分子机制；利用动物模型和临床试验证实锰联合PD-1抑制剂方案治疗复发难治性实体瘤的临床安全性和可行性，并初步探索可能的疗效预判标志物。

Most of antitumor immunotherapy, represented by PD-1 inhibitor, have focused on enhancing T-cell responses, but innate immune activation is the key upstream event of the priming of tumor-antigen-specific T cells. Thus, harnessing innate immunity opens up new possibilities and development trend for exploitation of the next generation of immunotherapy. Current clinical trials of innate immune agonists are mainly administrated locally via intratumoral delivery. Aside from the limitation to those accessible tumors, it is challenging to demonstrate a durable abscopal effect in patients with multiple heterogenous distal tumors. To overcome these challenges, exploring novel innate immune agonists with systemic activity is of scientific and urgent clinical need. Our previous results confirmed that manganese not only activates anti-viral innate immunity via facilitating the cGAS-STING pathway, but also attenuates tumor growth in a xenograft mouse model. Furthermore, we have registered the clinical trial in the ClinicalTrials.gov database (identifier NCT02961101) to determine the safety and efficacy of the combination of manganese and PD-1 inhibitor in patients with relapsed/refractory malignancies. Therefore, we aim to confirm the activating effect of manganese on innate immune response and anti-tumor efficacy of PD-1 inhibitor from clinical samples, animal tumor-bearing models and cultured cells; to analyze the key cellular and molecular mechanisms of regulatory effect utilizing single-cell RNA-seq analysis; to establish and optimize the regimen of manganese plus PD-1 inhibitor in patients relapsed/refractory epitheliogenic malignancies, and to dig the potential predictive biomarkers.