自噬调控PD-L1的机制研究及其在胃癌靶向治疗中的应用

Targeting immune checkpoints such as the one mediated by programmed cell death protein 1 (PD-1) and its ligand PD-L1 have been approved for treating human cancers with durable clinical benefit. However, many cancer patients fail to respond to anti-PD-1/PD-L1 treatment, and the underlying mechanism(s) is not well understood. Recent studies revealed that response to PD-1/PD-L1 blockade might correlate with PD-L1 expression levels in tumor cells. Hence, it is important to mechanistically understand the pathways controlling PD-L1 protein expression and stability, which can offer a molecular basis to improve the clinical response rate and efficacy of PD-1/PD-L1 blockade in cancer patients. Our results indicated that inhibition of autophagy increased the levels of PD-L1 in gastric cancer cells, suggesting that when autophagy was inhibited, the expression of PD-L1 might be reciprocally upregulated by tumor cells to defense against the immune surveillance, thus promoting the development of gastric cancer. . To test this hypothesis, we intend to perform in vitro and in vivo experiments, (1) to clarify the reverse regulation of autophagy on PD-L1, and demonstrate that tumor cells promote the development of gastric cancer by activating PD-L1 to reduce the level of autophagy; (2) Further explore the molecular mechanism of targeting autophagy and its regulation of PD-L1 in tumor therapy. This study will for the first time demonstrate that gastric cancer cells can use autophagy to regulate immune checkpoints to participate in immune response mechanisms, thus providing a theoretical basis and strategy for individualized treatment of gastric cancer with targeted autophagy and PD-L1.

靶向免疫检查点PD-1/PD-L1已在肿瘤治疗中显示较好疗效，然而仍有许多患者对治疗没有反应，且潜在机制尚不清楚。研究表明抗PD-1/PD-L1治疗反应与肿瘤细胞中PD-L1表达相关，因此明确肿瘤细胞PD-L1表达调控机制，为提高抗PD-1/PD-L1治疗临床反应率及疗效至关重要。申请者最新研究表明，抑制自噬能够促进胃癌细胞的PD-L1表达升高，这提示：当胃癌细胞自噬通路受到抑制时，可能反馈激活PD -L1的表达，进行免疫逃逸，促进胃癌发展。基于此，本课题拟采用体内和体外实验，明确自噬通路对PD-L1的反向调控作用，证明肿瘤细胞通过激活PD-L1应对自噬水平降低促进胃癌的发展;进一步探索靶向自噬通路及其调控的PD-L1在肿瘤治疗中的分子机制。本研究将首次阐明胃癌细胞能够利用自噬调控免疫检验点来参与免疫应答机制，从而为靶向自噬通路及PD-L1进行胃癌个体化治疗提供提供理论基础和解决策略。

靶向免疫检查点PD-1/PD-L1已在胃癌治疗中显示较好疗效，然而仍有部分胃癌患者对免疫治疗没有反应且潜在机制尚不清楚。研究表明抗PD-1/PD-L1治疗反应与肿瘤细胞中PD-L1表达相关，因此明确胃癌细胞PD-L1表达调控机制对于提高抗PD-1/PD-L1治疗临床反应率及疗效至关重要。本研究证明抑制自噬能够促进胃癌细胞的PD-L1表达升高，当胃癌细胞自噬通路受到抑制时，反馈激活了PD-L1的表达，进行免疫逃逸，促进胃癌发展。本课题采用了体内和体外实验，明确了自噬通路对PD-L1的反向调控作用，证明肿瘤细胞通过激活PD-L1应对自噬水平降低促进胃癌的发展;此外探索了靶向自噬通路影响NF-kappa B信号通路调控PD-L1在肿瘤治疗中的分子机制。通过本研究发现自噬相关蛋白如LC-3和p62与胃癌患者淋巴结浸润及PD-L1表达水平具有相关性，ATG4B的高表达与胃癌患者总体生存相关，并阐明了胃癌细胞能够利用自噬调控免疫检验点来参与免疫应答机制，为靶向自噬通路进行胃癌个体化治疗提供理论基础和解决策略。