负载CD134及CD137激动剂联合IL-36γ的纳米粒子抗黑素瘤的效应及机制研究

T cell tolerance largely dominates the inefficiency of anti-cancer immunotherapy. Agonists of dual costimulatory molecules CD134 and CD137 (DCo) boost different T cell activation, but still show a low response rate in melanoma treatment. Both the disability of DCo-induced tumor-specific T cell response in tumor microenvironment and the activation of regulatory T cells contribute to the poor prognosis of DCo therapy. IL-36γ is the vital mediator in skin local immune response. Published data and our previous results indicated that IL-36γ not only inhibits naïve T cell differentiation towards Treg, but also participates the non-specific T cell response with IFN-γ secretion. Our research further implied that DCo upregulate IL-36R receptor expression on T subsets in both the secondary lymphoid cells and melanoma-infiltrated tissue. Additionally, nanoparticles possess outstanding advantages in delivering the biomacromolecule like monoclonal antibodies, and unstable cytokines in application. Therefore, we put up the hypothesis that, the therapeutic nanoparticles which encapsulate DCo and IL-36γ will take synergistic function via non-specific T cell response activation and regulatory T cell inhibition, which greatly compensate for DCo shortcomings. The engagement of nanoparticle will further improve the biological efficiency of the drug combination in vivo. Our research will elucidate the effect and mechanism of our therapeutic nanoparticles, which will provide new strategies for melanoma therapy.

T细胞耐受是抗肿瘤免疫应答失效的重要原因。靶向T细胞CD134及CD137共刺激分子的激动剂（DCo）能够增强多种T细胞的效应，但在黑素瘤的治疗上仍存在反应率低等缺陷。这与DCo在肿瘤微环境中诱导的T细胞特异性免疫应答不足，以及对Treg细胞的激活有关。IL-36γ是调控皮肤局部免疫反应的关键分子，相关研究及我们前期的结果提示：IL-36γ不仅抑制初始T细胞向Treg细胞分化，还参与了诱导T细胞非特异性的免疫应答过程；此外我们还发现DCo可在次级淋巴结构及黑素瘤组织内上调T细胞IL-36R受体的表达。结合纳米粒子对于生物大分子的单抗及稳定性差的细胞因子体内递送上的优势，我们提出假设：搭载纳米粒子的DCo与IL-36γ免疫联用方案可分别针对T细胞非特异性免疫应答的激活和Treg细胞的抑制两方面的机制，巧妙的弥补DCo的缺陷，有望为黑素瘤的治疗提供新的策略。

T细胞耐受是抗肿瘤免疫应答失效的重要原因。我们前期的研究表明，靶向T细胞CD134及CD137共刺激分子的激动剂联用策略（DCo）能够有效的增强T细胞的免疫应答，特别是由IL-36g参与启动的非TCR依赖的固有免疫样应答作用，但该过程对CD134及CD137通路的依赖性，此过程对调节性T细胞的影响，以及其在抗黑素瘤治疗中的作用均尚不明确。我们的研究表明，与TCR依赖的T细胞激活效应不同，非TCR依赖的固有免疫样激活效应必须严格依赖于CD134+CD137通路的共同参与；且该过程中调节性T细胞也可发生功能逆转，释放肿瘤杀伤细胞因子IFN-g，并伴有CD4+Foxp3+细胞数目的显著减少。随后我们通过exTreg fate-mapping mice追踪启动固有免疫效应的调节性T细胞的去向，发现并无明显的CD4+Foxp3-细胞亚群的出现。此外，我们通过构建固有免疫样功能敲除鼠，验证了该效应在抗黑素瘤中的作用。最后，我们利用纳米粒子在药物体内递送上的优势，使用中空介孔硅同时搭载DCo与IL-36g的联用方案对黑素瘤进行免疫治疗。该新型免疫治疗策略有望为黑素瘤的治疗提供新的方向。

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