PGE2和肺癌发展相关，但其促癌机制尚待进一步研究。尽管免疫疗法已经成功地用于肺癌治疗，揭示免疫逃逸机制及寻求新的‘免疫检查点’仍是当前研究重点。本项目主要研究PGE2对T细胞特别是肿瘤浸润T细胞的影响及作用机制。我们前期研究揭示PGE2激活WNT途径，增强抗凋亡能力。结合最近研究发现PGE2与PD-1协同作用在病毒感染和肿瘤免疫过程中扮演重要角色，我们推测PGE2对肿瘤浸润T细胞有双相作用，一方面通过对T细胞代谢途径的影响增强PD-1信号途径对T细胞的抑制作用，另一方面通过激活T细胞WNT途径，促进记忆T细胞形成和抗凋亡能力，保存了T细胞抗肿瘤免疫反应的潜能。PGE2的作用可能与不同免疫表型T细胞表达不同的PGE2受体类型以及WNT途径激活状态相关。阐明PGE2/WNT途径对肿瘤浸润T细胞的影响有助于明确PGE2能否作为免疫治疗的新靶点并且对已开展的肺癌免疫治疗提供更合理的联合治疗方案。

Lung cancer is the leading cause of cancer-related deaths. Non-small cell lung carcinoma (NSCLC) accounts for 80-85% of all lung carcinomas. An increasing incidence of lung cancer has been observed in China. Inflammation has been postulated to play a key role in lung carcinogenesis. PGE2 has been implicated in apoptosis resistance, angiogenesis and enhanced invasion and metastasis. Thus, PGE2 has been considered to be involved in carcinogenesis. PGE2 and COX2 , the key enzyme in synthesis PGE2 , are the targets being studied for cancer therapy. However, multicenter phase II study in patients with NSCLC has concluded that inhibition of COX2 and PGE2 production in combination with chemotherapy did not improve progression-free survival, suggesting that the association of PGE2 and NSCLC is not fully understood. PGE2 plays important roles in regulating T-cell mediated immune responses. It is known that cancer immune escape is one of the hallmarks of cancer cells. In this proposal, we intent to investigate the effects of PGE2 on NSCLC from immune escape perspective, and we plan to examine how PGE2 affects the function of tumor infiltrating T cells and its underlying mechanisms. Recent studies show that the combined blockade of PGE2 and PD-1 has significantly improved the efficacy of the treatment of chronic virus infection and murine melanoma compared to using either inhibitor for PGE2 or PD-1 alone, suggesting the existing association between PGE2 and PD-1 mediated signaling pathways. But how the fate of tumor infiltrating T cells is determined through these two pathways is unknown. Our previous studies show that PGE2 promotes the activation of WNT pathway in naïve T cells and protects anti-CD3-stimulated T cells undergoing apoptosis. Based on recent findings and our own studies, in this proposal, we will explore the hypothesis that PGE2 plays double-edged sword in tumor immune escape. On one side, PGE2 inhbits effector function of T cells via down-regulation of glycolysis. On the other side, PGE2 promotes the generation of memory T cells and prevents activated T cells undergoing apoptosis via activation of WNT pathway thereby preserving the potential of T cell mediated anti-tumor immune response. We will undertake the following specific aims:.1).to investigate the role of PGE2 in regulating WNT pathway in phenotypically naïve, effector and memory T cells..2).to investigate the role of PGE2 in the differentiation and development of memory T cells.3).to investigate the anti-apoptotic effect of PGE2 in tumor infiltrating T cells and its underlying mechanisms..4).To investigate the interactions of PGE2 and PD-1 mediated signaling pathways in tumor infiltrating T cells and evaluate its clinical relevance.