SOST激活mTOR通路招募MDSC在骨转移肿瘤患者免疫检查点抑制剂治疗抵抗中的作用及机制研究

免疫治疗在多种实体瘤治疗中取得突破性进展，但获益人群依然有限。临床发现发生骨转移的肿瘤患者ICB治疗效果欠佳，但缺乏系统深入研究。本项目基于申请者前期发现：骨转移病灶中SOST表达显著高于原发灶；SOST过表达可导致肿瘤中CTLs浸润减少及功能受损，而MDSC招募增加；过表达SOST明显削弱了ICB抗肿瘤效果。基于以上工作基础并结合SOST的生物学特性提出假说：SOST可能通过激活mTOR信号通路促进MDSCs的招募，从而抑制CTLs的浸润和功能，最终导致骨转移患者免疫治疗抵抗。本研究通过深入研究SOST在骨转移灶诱导ICB抗体治疗抵抗的具体机制，为解决临床免疫治疗抵抗的难点问题及发展新型联合治疗策略提供理论依据。

The development of immunotherapy with immune checkpoint blockers (ICBs) has made an encouraging breakthrough in the treatment strategies of various solid tumors, while only a small proportion of patients will respond to the treatment. Clinical studies have found that cancer patients with bone metastases benefit little from ICB therapy, but lack of systematic and deep studies. This study is based on the applicant's previous findings: the expression of SOST in bone metastases is significantly higher than that in the primary lesions; overexpression of SOST can lead to reduced infiltration and impaired function of CTLs and increased recruitment of MDSC in tumors; overexpression of SOST significantly weakened the efficacy of anti-tumor effect of ICB. Based on the above work and combined with the biological characteristics of SOST, we speculated that SOST may promote the recruitment of MDSCs by activating the mTOR signaling pathway, thereby inhibiting the infiltration and function of CTLs, and ultimately restrains response of immunotherapy of patients with bone metastasis. This study provides a theoretical basis for solving the bottleneck problem of clinical immunotherapy resistance and developing new combined therapy strategies by further clarifying the specific mechanism of SOST in inducing ICB therapy resistance of patients with bone metastases.