SENEX基因触发的细胞衰老促进复发/难治弥漫大B细胞淋巴瘤免疫逃逸

Cellular senescence is generally considered as an important natural tumor barrier, is helpful to control tumor. However, as research deepens, found that aging does not necessarily lead to permanent, irreversible cessation of cell growth or to apoptosis. During repairing the abnormal genes in senescent cells, the Gene unstability and reprogramming and the genetic damage pressure such as radio-chemotherapy may make opportunities for create new oncogenes and drug resistance. This possibly made the senescent cell reviving and more proliferating, and the secreting phenotype can interfere with the immune function and facilitate tumor immune escape. We found previously that the relapsed/refractory DLBCL is closely related to the increased and infiltrated inhibitory immunologic cells and cytokines, and the stress induced cell senescence by SENEX gene triggered after drug stimulation has anti-apoptotic and immune-suppressing effect. So we speculate that the SENEX gene triggering senescence is the one of mechanisms for promoting immune escape in relapsed/refractory DLBCL, and will research it in clinical, cellular and animal models three levels using cell culture, molecular biology techniques, such as. DLBCL is the most common in adults Lymphoma, now the relapsed/refractory type hasn’t specially effective treatment, this study may be useful for preventing relapse and developing new immune-targeted treatment. No similar study has been reported till now.

一般认为细胞衰老是阻止肿瘤发生的一道重要天然屏障，有利于控制肿瘤。但随衰老研究加深，发现衰老并非一定导致细胞永久、不可逆性停止增殖，或走向凋亡，衰老过程中修复异常基因时的不稳定性和重编，及肿瘤细胞在接受放化疗等各种基因损伤压力时，可能为新致癌基因或耐药产生营造机会，乃至衰老瘤细胞复活、增殖力更强，其分泌表型等会干扰机体免疫功能，促进肿瘤免疫逃逸。我们前期发现复发/难治DLBCL与抑制性细胞和细胞因子浸润增多密切相关，药物等刺激后衰老基因SENEX触发的应力性衰老具有抗凋亡和免疫抑制效应，故推测SENEX触发的衰老是促进复发/难治DLBCL免疫逃逸机制之一，拟采用组织病理、细胞培养、分子生物学和基因工程等技术从临床、体外细胞水平和动物模型体内研究予以验证。DLBCL是成人最常见淋巴瘤，复发难治者无有效治疗方法，本研究对防止复发、开发新免疫治疗靶点有意义。未见类似研究报道。

复发难治是DLBCL患者死亡的主要原因，传统疗效差，近年有多种分子或免疫靶向新药使用，但长期疗效显示仍有很多患者最终难逃再复发、更难治而死亡，核心问题就是肿瘤细胞免疫逃逸。前期发现复发/难治DLBCL与抑制性细胞和细胞因子浸润增多密切相关，药物等刺激后衰老基因SENEX触发的应力性衰老具有抗凋亡和免疫抑制效应。本项目通过构建DLBCL的SIPS体内外模型和过表达或沉默SENEX基因模型，研究SENEX基因介导的SIPS在DLBCL细胞免疫逃逸中的作用及机制。结果表明：①临床相关研究显示SENEX基因触发的细胞衰老与临床DLBCL复发密切相关，SENEX基因激活的细胞衰老显著上调免疫抑制性细胞（Tregs，MDSCs和TAM）和衰老相关分泌表型，显著上调的免疫抑制性细胞和SASP参与r/r DLBCL患者外周血中复杂的肿瘤免疫微环境的形成。②通过体外SENEX过表达及沉默的细胞模型明确SENEX基因对DLBCL细胞系LY8的介导作用，SENEX通过活化p16/RB/E2F通路促进LY8细胞衰老；③体外实验证明SENEX基因介导的细胞衰老显著诱导免疫微环境中抑制性细胞群体和SASP累积逃避化疗杀伤，抵抗肿瘤细胞凋亡；④体内构建DLBCL动物模型，发现SENEX基因介导的细胞衰老通过诱导小鼠免疫微环境中MDSCs及抑制性细胞因子累积促进DLBCL肿瘤生长。因此，本研究提出SENEX基因触发的细胞衰老通过诱导周围免疫细胞向抑制性转化以及上调SASP，诱使周围环境从抗肿瘤效应转化为免疫逃逸，导致淋巴瘤细胞化疗抵抗，甚至复发、转移。这些结果对全面认识DLBCL复发和耐药机制、今后研发靶向新药、改善淋巴瘤治疗效果、最终遏制淋巴瘤具有重要意义。