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Progress in the Research on the Role of Tumor-associated Macrophages in Drug-resistance and Treatment of Tumors
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摘要: 肿瘤耐药的产生是肿瘤细胞与肿瘤微环境(tumor microenvironment, TME)相互作用的结果, 肿瘤相关巨噬细胞(tumor-associated macrophages, TAMs)是TME中的主要免疫细胞, 在炎症微环境和肿瘤细胞的恶性表型之间发挥桥梁作用, 与肿瘤耐药和疾病进展密切相关, 其中M2型TAMs浸润则预示着不良的临床结局。本文主要针对TAMs参与肿瘤耐药的作用机制和治疗进展进行综述, 以期为减少肿瘤耐药、增强抗肿瘤治疗疗效提供参考。Abstract: The development of drug-resistance is the interactional result between tumor cells and tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are the main immune cells in TME, and act as the bridge between the inflammatory microenviroment and malignant phenotype of tumor cells. They are closely related to drug-resistance and tumor progression, and the infiltration of M2 macrophages indicates a poor clinical outcome. This paper reviews the progress in research of the role of TAMs in drug-resistance and treatment of tumors, providing references for decreasing drug-resistance and increasing the curative effects.
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Keywords:
- tumor-associated macrophages /
- malignant tumors /
- drug-resistance /
- treatment
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患者与公众指南(patient and public versions of guidelines，PVG)，又称患者指南或患者版本指南[1]，国际指南协作网(Guideline International Network，GIN)将其定义为“将医务人员使用的临床实践指南(clinical practice guidelines，CPG)内容，转化成患者和公众更容易理解和使用的一种指导性文件”[2]。随着PVG的不断发展及对其认识的不断深入，部分中国学者认为其是“在循证医学理念的指导下，以患者与公众关注的健康问题为中心，以当前可获得的最佳证据为基础制订的、适合患者与公众使用的指南”[3]。PVG在帮助患者与公众获取疾病知识、为患者与公众提供医疗决策支持、提高患者对治疗的依从性、促进医患有效沟通，以及提高公众健康素养等方面发挥重要作用[4]。此外，严格遵从GIN定义研制的PVG，也有助于促进CPG的传播与实施[5]。
相对于国内，现阶段国外发布的PVG数量较多。截至2020年6月28日，国外已有超过600部PVG发布，主要由协(学)会制订，如苏格兰校际指南网络(Scottish Intercollegiate Guidelines Network，SIGN)、美国国家综合癌症网络(National Comprehensive Cancer Network，NCCN)、欧洲心脏病学会(European Society of Cardiology，ESC)等[1, 6]。截至2023年1月8日，笔者在PubMed、Web of Science、中国知网、万方数据知识服务平台、中国生物医学文献数据库共检索到17部中国学者制定的PVG；截至2023年3月31日，中国学者在国际实践指南注册与透明化平台(Practice guideline REgistration for transPAREncy，PREPARE)注册的PVG已达30部，主题涵盖了儿科疾病、风湿免疫性疾病、内分泌疾病、皮肤病等。尽管近年来我国注册、发表或发布的PVG数量在不断增加，但相较于CPG，其数量相对较少[7-9]，仍处于起步阶段[10]。为进一步促进PVG在国内的高质量发展，世界卫生组织指南实施与知识转化合作中心联合国内多家机构，于2021年在中国珠海举办了首届PVG方法学研讨会，并在会后发出了包括“加大PVG的方法学研究”在内的五项倡议[11]。德国维藤/黑尔德克大学Monika Becker等[12]也于2022年发表了项目计划书，拟对德国肿瘤患者进行访谈和焦点小组讨论，形成德国视角的PVG制订、传播与实施建议。总体而言，PVG仍需进一步研究和探索，尤其是在制订方法方面。
目前，PVG有两种常见的制订方法，即直接制订和改写制订[13]。直接制订是指采用和CPG相似的制订流程，重新确定患者与公众关注的问题，经全面检索证据后形成PVG；而改写制订是指未重新收集、遴选和确定问题，仅以某部CPG为基础，对其推荐意见进行改写并形成PVG。为进一步推动我国PVG的发展，本文拟对上述两种制订方法进行探讨，并以案例形式进行介绍，以期为PVG的制订提供参考。
1. 直接制订
该方法的优势在于临床问题调研阶段即考虑患者与公众的观点和意愿，确保PVG中的问题均为患者与公众最为关注的健康问题，解决患者与公众对疾病知识的实际需要，但该方法的制订周期较长，所需经费及人力投入也较多。直接制订PVG的一般流程详见图 1[14]。
就证据检索与筛选而言，目前已发表的PVG仍存在较大差异，部分PVG纳入的文献类型包括CPG、专家共识、系统评价/Meta分析、随机对照试验、队列研究、病例对照研究、病例系列和病例报告等[15]；部分PVG纳入的文献类型为CPG、专家共识、系统评价/Meta分析[16-17]；此外，部分PVG纳入的文献类型仅为CPG和专家共识[18]。造成上述差异的原因可能为PVG方法学的缺失，导致不同制订者对证据的理解和认识不同。然而，纳入证据的类型、范围在一定程度上可能影响指南制订的工作量和最终的推荐意见。若PVG制订工作组的规模(包括人数、专家代表性等)与CPG接近，笔者建议纳入系统评价/Meta分析、随机对照试验和队列研究等，进而回答目前CPG中无相关推荐意见的临床问题，形成科学、专业、权威的推荐意见；若工作组的规模与CPG存在较大差距，或在资源有限的情况下，可考虑仅检索CPG和专家共识。
笔者所在课题组曾参与制定了《中国儿童消化道异物管理指南(患者与公众版，2022)》[15]，该PVG采用了直接制订的方式。相较于CPG[19]，该指南在制订流程方面作了以下调整：(1)在指南制订工作组中，增设了患者与公众组。(2)在临床问题收集与遴选方面，收集临床问题时，特别收集了患者与公众关注的问题；遴选临床问题时，以患者与公众对问题重要性的判断为主。(3)在证据检索与遴选过程中，对CPG进行检索，且将CPG视为证据，若CPG中已有患者与公众关注问题的答案，可直接进行引用；若无，则依次检索系统评价/Meta分析和原始研究。(4)在证据质量分级和推荐强度分级方面，考虑到使用者为患者与公众，指南内容(包括证据质量分级和推荐强度分级的呈现)不宜过于复杂，因而未呈现证据质量分级，仅呈现推荐强度分级，推荐强度根据推荐意见的共识度确定，以形象化的“笑脸符号”表示，“笑脸符号”越多，表示推荐强度越高。(5)形成推荐意见时，考虑了推荐意见的表述是否通俗易懂，因而在进行德尔菲法调研时，同步调研了患者与公众对推荐意见的可理解性，以及其建议或意见。(6)在撰写指南全文时，遵循患者与公众指南的报告规范(Reporting Items for Practice Guidelines in Healthcare-Public or Patient Versions of Guidelines，RIGHT-PVG)[20]。(7)在指南的传播与实施过程中，考虑到使用人群为患者与公众，因而扩大了传播途径，更多借助社交媒体的力量开展宣传和推广，如在《协和医学杂志》、西安市儿童医院等微信公众号平台发布漫画版指南。
2. 改写制订
该方法的优势在于制订周期较短，可较快形成PVG，传播CPG中临床医生、患者与公众认为比较重要的疾病知识。国外大多采用改写制订的方法进行PVG的制订，将已发表CPG中的推荐意见进行改写，形成PVG，亦是对CPG传播与实施的重要方式。但考虑到该方法中的CPG在遴选临床问题时，可能未充分考虑患者与公众的观点与意愿，改写后的PVG可能并不能全面解答患者与公众关心的问题[21]。基于《GIN公众工具包：患者与公众参与指南》对于PVG制订方法的介绍和笔者参与PVG制订的实际经验[2, 21]，现对改写制订PVG的一般流程进行总结，详见图 2。
笔者所在课题组曾参与制定了《中国儿童咳嗽指南(2021患者版)》[21]，该PVG的制订方法采用了改写制订方式，制订的核心环节是推荐意见的形成和患儿家长意见的调研。在形成推荐意见时，所有推荐意见均来源于《中国儿童咳嗽诊断与治疗临床实践指南(2021版)》[22]。需注意的是，该部PVG采用形象化、不同程度和数量的“笑脸符号”对源指南使用的推荐分级的评估、制订与评价(Grading of Recommendations, Assessment, Development and Evaluations, GRADE)系统进行了转化。GRADE分级系统将证据质量分为高、中、低和极低4个等级，分别用A、B、C、D表示，推荐强度分为强、弱2个等级，分别用1和2表示。而在PVG中，用“大笑符号”表示强推荐，“微笑符号”表示弱推荐，1~4个“笑脸符号”分别表示极低质量、低质量、中等质量和高质量证据。如CPG中的低质量证据弱推荐(2C)，
在PVG中用2个“微笑符号”表示；CPG中的中等质量证据强推荐(1B)在PVG中用3个“大笑符号”表示(表 1)。同时，采用思维导图的形式呈现推荐意见，以促进患者与公众对推荐意见的正确理解。在开展患儿家长意见调研时，采用焦点小组讨论法，招募自愿参加、有正常理解和沟通能力的咳嗽患儿照护者参与讨论，主持人根据访谈提纲引导患儿家长完成焦点小组讨论，从而确保推荐意见的可理解性。
表 1 临床实践指南和患者与公众指南对GRADE分级系统的呈现分类 GRADE分级系统呈现方式 临床实践指南 1A 1B 1C 1D 2A 2B 2C 2D 患者与公众指南 
注：GRADE：推荐分级的评估、制订与评价；1：推荐强度为强；2：推荐强度为弱；A：证据质量为高；B：证据质量为中；C：证据质量为低；D：证据质量为极低； 
3. 制订方法比较
直接制订和改写制订作为当前制订PVG的两种方法，虽存在差异，但亦有相同之处。两种方法均需关注制订过程中的潜在利益冲突，以及制订完成后PVG的传播与实施。但两种方法在资源投入方面存在较大差异，直接制订可能在各方面均需较多的资源。此外，在临床问题、证据等方面也存在差异，详见表 2。
表 2 直接制订与改写制订患者公众指南的异同制订过程 直接制订 改写制订 注册与撰写计划书 制订初期完成 制订初期完成 组建工作组和管理利益冲突 组建新的专家组，需纳入患者与公众代表，同时对利益冲突进行管理 基于原有专家组进行调整，补充患者与公众代表，同时对利益冲突进行管理 临床问题 邀请患者与公众参与临床问题收集和遴选 临床问题来源于源指南 证据 全面检索证据，可将不同指南的推荐意见、系统评价和原始研究结果作为证据 证据来源于源指南 推荐意见 基于证据形成易于理解的推荐意见，并对推荐意见达成共识 沿用源指南中的推荐意见，但需对表述进行调整 证据质量分级和推荐强度分级 对每条推荐意见的证据质量和推荐强度进行分级，采用患者与公众易于理解的符号表示 沿用源指南中每条推荐意见的证据质量和推荐强度分级，采用患者与公众易于理解的符号表示 撰写 遵循RIGHT-PVG 遵循RIGHT-PVG 外审 需要(确保推荐意见内容和表述准确) 需要(确保改写后的推荐意见内容相较于源指南未改变) RIGHT-PVG：患者与公众指南的报告规范 4. 制订方法选择
国内PVG采用直接制订方法的比例较高，也有部分PVG采用改写制订方法，如《中国儿童咳嗽指南(2021患者版)》《中国居民家庭幽门螺杆菌感染的防控和管理专家共识(科普版，2021年)》[21, 23]。若采用改写制订方法，需在源CPG制订时同时规划PVG的制订工作，由于国内指南制订者对PVG的认知度较低[10]，因而此类PVG的数量较少。
选择PVG制订方法时，需考虑以下两个方面：(1)不同方法制订出的PVG可发挥不同的作用，因而在选择制订方法时需考虑PVG的主要目的。若PVG的主要目的是为促进CPG的传播与实施，则可考虑选择“改写制订”。若PVG的主要目的是为解决患者与公众关注的疾病相关问题，则可考虑选择“直接制订”。(2)不同方法对制订团队有着不同的要求。非源指南制订者若采用“改写制订”方法制订PVG，可能存在知识产权等问题，建议与源指南制订者进行充分沟通。
5. 小结
PVG相较于其他健康宣教工具，融入了循证医学思维，其内容具有科学性、专业性和权威性[4]。尽管目前已有两种具备基本框架的PVG制订方法，但PVG的制订仍面临诸多挑战，如目前尚无针对PVG广泛使用的证据质量和推荐强度分级系统，专家组的组建方案、患者与公众的参与人数尚缺乏明确共识，尚无PVG的方法学质量评价工具等，建议CPG制订者以及致力于健康教育的研究者给予PVG更多关注，积极参与PVG的制订、传播、实施及方法学研究，以推动PVG在我国的高质量发展。
作者贡献：苏鹏飞、于健春共同参与论文选题；苏鹏飞负责文献检索及论文撰写；于健春负责论文修订。利益冲突：所有作者均声明不存在利益冲突 -
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