Role of SWI/SNF Complex Subunit Abnormality in Tumors and Progress of Related Therapeutic Strategies
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摘要:
SWI/SNF复合物是调节真核细胞基因表达的一种重要而复杂的多亚基蛋白复合物，广泛参与信号转导、细胞周期及分化等各种生物过程，其亚基基因在20%以上的恶性肿瘤中发生突变。本文综述了该复合物及其亚基在恶性肿瘤中的作用和特征，并探讨SWI/SNF复合物在肿瘤治疗中的潜在临床应用。
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关键词:
- 恶性肿瘤 /
- SWI/SNF复合物 /
- 致癌机制 /
- 治疗策略
Abstract:The SWI/SNF complex is an important multi-subunit protein complex that regulates gene expression in eukaryotic cells. It is widely involved in various biological processes such as signal transduction, cell cycle and cell differentiation. SWI/SNF complex subunit mutations occur in more than 20% of malignant tumors. This article reviews the role and characteristics of this complex and its subunits in malignant tumors, and explores the potential clinical application of SWI/SNF complexes in tumor therapy.
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Key words:
- Malignant tumor /
- SWI/SNF complex /
- Carcinogenic mechanism /
- Treatment strategy
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0 引言
多发性骨髓瘤（multiple myeloma, MM）是浆细胞的恶性克隆增殖性疾病，表现为骨髓中大量恶性浆细胞的增殖和聚集，分泌单克隆的免疫球蛋白或其片段（M蛋白），导致贫血、肾功能不全、骨质破坏等一系列临床症状[1]。进入本世纪以来，由于自体干细胞移植的开展和靶向药物如蛋白酶体抑制剂（硼替佐米、伊沙佐米、卡非佐米）、免疫调节剂（沙利度胺、来那度胺、泊马度胺）和免疫治疗（单克隆抗体、CAR-T以及CAR-NK等）的应用，MM治疗的效果出现前所未有的改观，有效率升高，生存期延长[2-3]。然而总体而言MM仍然是一种不能被治愈的疾病，大多数患者最终难逃复发的厄运，并且随着复发次数增多，瘤细胞的耐药性增强，最终复发而不治[4]。为此，有必要对MM的发病机制和治疗策略进行回顾和梳理，以进一步改进其治疗方法，最终达到治愈MM的目标。
1 骨髓免疫微环境对于MM发生、发展的重要性
MM主要生长在骨髓中的恶性肿瘤，复杂的骨髓瘤微环境中的细胞和非细胞组分对骨髓瘤细胞的生长与存活起到独特的维持作用，特别是骨髓微环境中的免疫细胞（包括T细胞、自然杀伤细胞、单核-巨噬细胞、树突状细胞、髓源抑制细胞等），不仅失去对恶性转化的骨髓瘤细胞的免疫监督和免疫杀伤作用，而且会在骨髓瘤细胞的影响下，发生功能失调，甚至促进和维系骨髓瘤生长和存活，诱导耐药的产生，导致疾病的反复复发[5-6]。
研究表明，在发展至活动期之前，MM都要经历意义未明的单克隆丙种球蛋白血症（monoclonal gammopathies of undetermined significance, MGUS）和冒烟型多发性骨髓瘤（smoldering MM, SMM）阶段[7-8]。尽管在MGUS和SMM中检测到的遗传损伤（如基因突变、染色体易位和拷贝数的改变等）与MM相似，但并非所有的MGUS和SMM都会发展为活动性MM。尤其是MGUS人群，每年只有大约1%发展为MM，大多数个体将终生保持这种意义未明的状态[9]。在MGUS向SMM和活动性MM的发展过程中，骨髓微环境中的免疫细胞的功能状态也会发生失调，如具有干性记忆性特征的T淋巴细胞耗尽以及具有衰老与耗竭特征的T淋巴细胞的积累，而且其程度随着病情进展而加重。耗竭T细胞的特点是效应功能丧失，抑制性受体表达增高，表观遗传和转录谱改变，代谢方式改变，难以有效发挥杀伤骨髓瘤细胞的效能。T细胞耗竭是患者免疫功能障碍的主要原因之一[10-12]。进一步研究显示，经过治疗达到完全缓解甚至是微小残留病阴性患者中，其骨髓中免疫细胞功能状态与患者的无进展生存密切相关。说明单凭克隆性浆细胞的内部因素（基因组的改变）不足以驱动MM的发生、发展。骨髓免疫微环境在MM的发生、发展中发挥着至关重要的作用[13]。
MM的发生、发展是一个多因素作用下的多步骤、复杂、动态的进化过程。具体而言，多克隆浆细胞在一些起始性的突变（如IgH易位、13q-、高二倍体等）驱动下，获得生长优势，成为单克隆的浆细胞。克隆性浆细胞为了获得更强的增殖和生存能力，一方面必须适应骨髓的微环境，发生新的遗传学和表观遗传学变化，使细胞内部增殖信号激活，凋亡信号受到抑制，并在营养竞争、免疫逃逸方面相对于正常细胞有显著的优势；另一方面瘤细胞要对骨髓微环境进行改造，使其有利于自身的生长[14-16]。瘤细胞和免疫细胞的相互作用及其生物学特性的改变都是动态变化的。骨髓瘤细胞可以表达许多能够与免疫细胞相互作用的分子，例如在骨髓瘤细胞基因组中检测到的激活诱导的胞苷脱氨酶（activation-induced cytidine deaminase, AID），其表达水平可以受到树突状细胞核因子κB受体活化因子配体（receptor activator of nuclear factor kappa-B ligand, RANKL）的调控，提示基因组的不稳定性与MM肿瘤微环境之间可以发生直接的相互作用[17]。此外，MGUS和MM细胞还可以表达钙连蛋白、钙网蛋白以及PD-L1分子，以抑制免疫细胞的功能[18]。
免疫系统对于早期肿瘤的免疫监督可以分为三个阶段，即消灭、平衡和逃逸，简称3E[19]。在Vk*MYC小鼠骨髓瘤模型中，T细胞和NK细胞可以通过CD226作用于肿瘤细胞，产生穿孔素和γ干扰素以杀伤骨髓瘤细胞，发挥免疫监督的功能[20]。也有学者报道对MM患者进行同基因造血干细胞移植时，加用免疫检查点分子TIGIT抗体可以防止CD8+T细胞的耗竭，延迟病情复发[21]。研究表明，不仅MM患者体内存在瘤细胞特异性的细胞毒性T淋巴细胞和特异性抗体，而且处于MGUS阶段的克隆性浆细胞可以被免疫细胞所识别并激活免疫细胞，这些个体体内可以检测到MGUS特异性的CD4+和CD8+淋巴细胞介导的免疫反应[22]。但随着MM的发展进程，干样记忆性T细胞的消耗并逐渐衰老与耗竭，这些免疫反应似乎不能完全遏制肿瘤的蔓延。MM患者的骨髓NK细胞激活型受体NKG2D、NCR3和CD244的表达降低，而PD-1表达增高，提示这些分子参与了MM的免疫逃逸，也可能是MM免疫治疗的潜在靶点[17]。
2 对靶向骨髓免疫微环境治疗MM的策略思考
越来越多的证据表明，MM的发展进程取决于瘤细胞的进化及其生长的生态系统，其中免疫微环境所扮演的角色日益受到重视。治疗MM，不仅要瞄准骨髓瘤细胞本身，还应该关注骨髓瘤赖以生存的免疫微环境。在当下的靶向和免疫治疗时代，MM的治疗有效率不断提高，缓解深度越来越深，此时更应关注如何调动机体的免疫监督功能，使MM达到长期、持续的缓解，乃至治愈[23]。
近年来，不少新型治疗产品在MM的治疗领域取得令人瞩目的效果。这些新型产品往往在杀灭骨髓瘤细胞的同时，对免疫功能也有强大的调控作用。例如，抗CD38单克隆抗体不仅可以通过抗体依赖细胞介导的细胞毒作用（antibody-dependent cell-mediated cytotoxicity, ADCC）和补体依赖的细胞毒作用（complement-dependent cytotoxicity, CDC）杀伤骨髓瘤细胞，还可以中和CD38的胞外酶活性，减少免疫抑制介质腺苷的产生，同时对表达CD38的免疫抑制细胞也有清除作用[24]。抗CS-1单克隆抗体在杀灭骨髓瘤细胞的同时，还可以与NK细胞表面CS-1结合并激活NK细胞，使之发挥更强大的ADCC效应[25]。刚刚获批或正在研发CAR-T、CAR-NK和双特异性抗体（Bi-specific antibody, BiTEs）药物则是采用基因工程手段来重新激发免疫系统，达到消灭骨髓瘤细胞的目的[26]。
目前的免疫治疗仍然不能根治MM。在研发免疫治疗策略时，以下几点应该引起关注：首先，从理论上讲，实施免疫治疗应该是在疾病的早期开展，因为在疾病早期免疫系统功能处于相对正常状态，能够最大程度地发挥免疫监督功能。在此阶段，倘能通过应用疫苗阻止MGUS向MM的进展，将会达到事半功倍的效果[27]；其次，应注意纠正免疫功能的失调。大量研究显示，MM微环境中的免疫细胞处于衰老、耗竭或失能状态，不能有效发挥杀伤骨髓瘤细胞的效能。为此，人们尝试应用靶向PD-1/PD-L1以及其他的免疫检查点如LAG3、TIGIT的抑制剂MM治疗，然而相关临床试验的结果并不理想[28]。提示我们需要寻找新的靶点或探索新的治疗策略，如将免疫检查点抑制剂与其他抗骨髓瘤治疗药物进行联合运用；第三，在接受免疫治疗的机体内，残存的肿瘤细胞也会不断进化，导致对免疫治疗产生耐受。例如，接受抗CD38单抗治疗后复发的患者体内骨髓瘤细胞CD38的表达会明显下调[29]。接受BCMA-CAR-T细胞治疗后复发的患者其瘤细胞BCMA的表达也会显著减少[30]。为此，可在深入研究骨髓瘤细胞靶抗原表达调控的基础之上，采用一些小分子化合物使MM丢失的抗原重新表达，逆转其对免疫治疗的耐受性或恢复其敏感度；最后，深入开展骨髓瘤细胞与免疫微环境相互作用的基础研究。骨髓瘤细胞克隆内的异质性导致其抑制免疫细胞的机制可能有所不同，对免疫细胞功能的影响也会有差异[31-32]。当前各种组学技术在阐明骨髓瘤细胞与免疫细胞的相互作用机制方面有着独特的优势。只有充分阐明免疫微环境的生物学特性，才能有针对性地纠正免疫功能异常，使MM获得长期、持续的缓解乃至治愈。
3 总结
多发性骨髓瘤治疗研究发展至今已经取得不少里程碑式的进展，但仍未能实现治愈性目标。患者反复复发的根本原因在于肿瘤细胞与微环境之间发生动态相互作用，使机体免疫系统失去了对肿瘤识别和杀伤的能力。目前，骨髓瘤治疗的焦点已不仅仅局限于针对肿瘤细胞本身，更多的研究聚焦于重塑个体的抗肿瘤免疫，达到免疫正常化。
道阻且长，行将终至。相信随着人们对MM及其免疫微环境相互作用研究的不断深入，MM免疫治疗效果一定会有进一步提升，治愈MM的目标终将能够实现。
作者贡献郭庆：文献整理及撰写饶秋、周志毅：指导论文撰写 -
表 1 SWI/SNF复合物亚基在恶性肿瘤中的变异情况
Table 1 Abnormality of SWI/SNF complex subunits in malignant tumors
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