免疫编辑诱导的免疫治疗耐药
作者简介:
吕丽（1988-），女，硕士，医师，主要从事肺癌、免疫治疗研究
林劼 昆明医科大学第二附属医院肿瘤科主任、学术带头人。主要从事肺癌、乳腺癌、胰腺癌、结直肠癌及胃癌等肿瘤的综合诊治。中国临床肿瘤学会（CSCO）第三届理事会理事、云南省抗癌协会临床肿瘤学协作专业委员会主任委员、云南省医师协会临床精准医疗专业委员会主任委员、中国抗癌协会第一届肿瘤放射防护专业委员会常务委员、CSCO青年专家委员会委员、CSCO肝癌专业委员会委员、中国研究型医院学会分子肿瘤与免疫治疗专委会常委、中国医师协会肝癌专业委员会委员、中华医学会医学细胞生物学分会青年委员会委员、国际肺癌研究学会（IASLC）会员、西部放射治疗协会胸部肿瘤放射治疗专委会委员、云南省医师协会肿瘤转化医学医师分会副主任委员、云南省预防医学会肺癌专业委员会副主任委员、云南省医师协会乳腺癌专业委员会副主任委员、云南省医师协会肿瘤转化医学医师分会副主任委员等。近5年共发表论文20余篇，并有5篇被SCI收录。主编专著3部，主持并参与国家自然基金项目3项，主持CSCO基金1项，中国健康促进基金会抗血管生成研究项目1项，云南省联合基金专项1项。获得专利3项，获云南省科学技术进步三等奖1项
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通讯作者:
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摘要:
近年来，免疫治疗在多种恶性肿瘤治疗中取得突破性进展，为肿瘤患者带来明显生存获益。然而，免疫系统在识别和杀伤肿瘤细胞的同时，出现免疫编辑诱导，导致大多数患者对免疫治疗具有先天或后天的耐药性。肿瘤免疫编辑是免疫系统抑制或促进肿瘤发生发展的过程，肿瘤的发生发展经历了免疫消除、免疫平衡和免疫逃逸三个阶段。在整个过程中，肿瘤的免疫原性被编辑，并获得使疾病进展的各种免疫抑制机制，致使肿瘤细胞逃避免疫系统的监测，导致肿瘤细胞免疫逃逸产生耐药。因此，揭示肿瘤免疫治疗耐药机制及克服耐药至关重要。本文主要从肿瘤免疫编辑过程背后的机制对肿瘤免疫治疗耐药作一具体阐述，为临床中克服免疫耐药取得更好疗效提供参考。
Abstract:In recent years, immunotherapy has made breakthrough progress in the treatment of multiple malignancies, which has brought significant survival benefits to cancer patients. However, while the immune system recognizes and kills tumor cells, there is immune editing induction, which leads to the innate or acquired resistance of most patients to immunotherapy. Tumor immunological editing is a process in which the immune system inhibits and promotes the development of tumors. The occurrence and development of tumors have gone through three phases: immune elimination, immune balance and immune escape. In the whole process, the immunogenicity of tumor has been edited, and various immunosuppressive mechanisms have been obtained to make the disease progress, which made tumor cells escape from the monitoring of the immune system, leading to the immune escape of tumor cells producing immunotherapy resistance. Therefore, it is important to reveal the mechanism of tumor immunotherapy resistance and how to overcome resistance. In this paper, the mechanism behind the editing process of tumor immunity is discussed in detail to provide references for overcoming immune resistance in clinical practice and achieving better efficacy.
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Key words:
- Tumor /
- Immunoediting /
- Immunotherayp /
- Immune checkpoints /
- Tumor microenvironment /
- Drug resistance
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0 引言
鼻咽癌又称“广东瘤”，在我国南方发病率较高，其中男性发病率超过20/10万，女性超过10/10万。在东南亚、北非、中东和北极地区，以及亚洲和太平洋岛屿上的移民人口中，发病率略低于我国南方，而在世界其他地区，这一比率普遍低于1/10万[1]。随着调强放射治疗技术及同步化疗的应用，鼻咽癌的预后得到明显提高。目前Ⅰ期鼻咽癌患者5年总生存率高达96%，但局部晚期鼻咽癌患者5年总生存率仍不理想，远处转移是治疗失败的主要模式，相较T分期，N分期是影响远处转移的主要因素[2-5]。Xu等[4]报道181例经同步放化疗的局部晚期鼻咽癌患者预后，全组分3亚组T3~4N0~1M0、T1~2N2~3M0、T3~4N2~3M0 ，三组3年无远处转移率分别为89.6%、75.7%和76.3%（P=0.028），笔者认为在目前调强技术和铂类同期化疗的背景下，鼻咽肿瘤局部晚期（T3~4期）预后明显优于局部区域晚期（N2~3期），基于N分期的分层治疗较为合适。因此如何进一步提高N2~3期局部晚期鼻咽癌患者的总生存率，降低远处转移率是目前临床研究热点。本研究回顾性分析我院收治的N2~3期局部晚期鼻咽癌患者临床资料，探讨患者预后影响因素，比较不同新辅助化疗疗程预后差异。
1 资料与方法
1.1 临床资料
2012年1月—2013年12月广州医科大学附属肿瘤医院收治的18~70岁、病理证实、临床资料完整、临床分期为T1~4N2~3M0（UICC/AJCC第6版分期）的局部晚期鼻咽癌，剔除同时合并其他恶性肿瘤、存在严重的内科合并症、重要脏器（心、肺、肝、肾）功能不全的病例，共270例患者纳入本次研究。全部患者均有2~3种影像学检查以诊断鼻咽病灶及区域淋巴结的分期并排除远处转移（如肝转移、肺转移或骨转移等），包括鼻咽+颈部MRI、胸片、CT、PET-CT以及核素骨扫描。270例患者中，男200例、女70例，中位年龄46岁。局部病变分期手段：235例行鼻咽+颈部MRI、27例行鼻咽+颈部CT、8例行PET-CT分期。全组病理类型分为：鼻咽未分化型非角化性癌155例（57.4%）、鼻咽低分化型非角化性癌100例（37.0%），鼻咽角化性鳞癌15例（5.6%）。临床分期T1、T2、T3、T4分别为17例（6.3%）、93例（34.4%）、114例（42.2%）及46例（17.0%）。临床N2、N3分别为235例（87.0%）、35例（13.0%）。
1.2 治疗方案
新辅助化疗方案：化疗方案为DP（多西他赛75 mg/m2第1天+顺铂或奈达铂75 mg/m2第1天）、PLF（顺铂或奈达铂75 mg/m2+氟尿嘧啶300~500 mg/m2第1~5天+亚叶酸钙200 mg/m2第1~5天）、TP（紫杉醇175 mg/m2第1天+顺铂或奈达铂75 mg/m2第1天）及TPF（多西他赛60 mg/m2第1天+顺铂或奈达铂60 mg/m2第1天+5-Fu 500 mg/m2第1~5天），每3周重复。本研究将顺铂与奈达铂合计一组统计。全组依据NCT化疗疗程数分为：NCT≥3程（84例）、NCT=1~2程（106例）、NCT=0程（80例）患者分别为84例、106例和80例。
根治性放疗：采用调强放射（IMRT）技术，放疗剂量：原发病灶（GTVnx）70~72 Gy/30~32次，颈部淋巴结（GTVnd）64~70 Gy/30~32次，高危预防区（CTV1）60 Gy/30~32次，低危预防区（CTV2）50~54 Gy/30~32次；依据肿瘤消退情况，部分患者经放化疗后鼻咽残留病灶或转移淋巴结残留病灶局部加量8~10 Gy/4~5次，或行1次γ刀5 Gy/次。靶区勾画及正常组织的保护参照RTOG标准。同步化疗方案：顺铂或奈达铂每周（40 mg/m2第1天，共6~7程）或三周方案（75 mg/m2第1天，共2~3程），多西他赛+铂类（多西他赛75 mg/m2第1天+顺铂或奈达铂75 mg/m2第1天，3周方案，共2~3程）。放疗同期进行。本研究将放疗前7天内、或放疗结束后7天内化疗均定义为同期化疗。
1.3 统计学方法
统计分析采用SPSS19.0软件。定量资料比较采用Wilcoxon rank秩和检验，定性资料比较采用卡方及Fisher精确检验，采用Kaplan-Meier生存函数比较生存率、绘制生存曲线，各组生存率比较应用Log rank检验，Cox回归进行单、多因素分析。以P < 0.05为差异有统计学意义。
2 结果
2.1 化疗疗程资料
全组行5、4、3、2、1程新辅助化疗分别为1（0.4%）、2（0.7%）、81（30%）、101（37.4%）及5（1.9%）例，行单纯同期放化疗为80（29.6%）例。因本研究行5、4、1程新辅助化疗病例较少，故将行新辅助化疗3、4、5程合并一组，行新辅助化疗1、2程新辅助化疗者合并一组。不同新辅助化疗疗程临床资料比较，见表 1。
表 1 N2~3期局部晚期鼻咽癌患者不同新辅助化疗疗程临床资料比较n(%)Table 1 Comparison of cllinical data of stage N2-3 locally advanced nasopharyngeal carcinoma patients among three groups n(%)
2.2 全组预后
总生存期（OS）、无病生存期（DFS）、无局部复发生存（LRFS）、无远处转移生存（DMFS）均定义为从明确诊断日期开始到任一事件发生日期或末次随访日期。末次随访日期为2018年4月30日。全组中位随访时间63月（6~75月）。全组死亡57例（21.1%）。全组单纯局部复发6例（2.2%），2例颈部淋巴结复发，4例鼻咽原发灶复发，单纯远处转移54例（20%），同时出现局部复发和远处转移（鼻咽病灶复发+肺肝转移）1例（0.4%）。全组5年OS、DFS、LRFS和DMFS分别为78.4%、77.8%、97.7%和79.5%。
2.3 鼻咽癌患者不同疗程新辅助化疗的预后
鼻咽癌患者不同疗程新辅助化疗5年OS、DFS、DMFS差异有统计学意义，NCT≥3程新辅助化疗的预后明显优于另外两组疗程，LRFS差异无统计学意义，见表 2。
表 2 N2~3期鼻咽癌患者不同新辅助化疗疗程5年预后比较Table 2 Comparison of 5-year prognosis of N2-3 nasopharyngeal carcinoma patients among three groups
2.4 影响无远处转移率的单因素、多因素分析
单因素分析显示新辅助化疗疗程、N分期和年龄是影响无远处转移生存率的主要因素，见表 3。将单因素分析中有意义的临床因素进行多因素分析，结果提示新辅助化疗疗程、N分期、年龄均是治疗后有无转移的独立预后因素，见表 4。
表 3 影响N2~3期局部晚期鼻咽癌无远处转移率的单因素分析Table 3 Univariate logistic analysis of clinical factors for DMFS in N2-3 locally advanced nasopharyngeal patients
表 4 N2~3期局部晚期鼻咽癌无远处转移生存率影响因素多因素分析Table 4 Univariate logistic analysis of clinical factors for DMFS in N2-3 locally advanced nasopharyngeal patients
2.5 不良反应
全组均顺利完成治疗。其中NCT≥3程3~4度骨髓抑制者21例（25%）、NCT=1~2程28例（26.4%），NCT=0程23例（28.8%），差异无统计学意义（P=0.165）。
3 讨论
本研究结果显示NCT≥3程新辅助化疗的N2~3期局部晚期鼻咽癌患者的5年总生存、无瘤生存、无远处转移均优于行2程或单纯同期放化疗的患者，且可顺利完成治疗。
目前NCCN对局部晚期鼻咽癌的治疗推荐并无分层治疗，其建议对局部晚期鼻咽癌即临床分期为Ⅱ~ⅣB期即T1、N1~3M0或T2~T4、N0~3M0的患者治疗以同期放化疗为主，新辅助化疗+同期放化疗为2A类证据[6]。其2A类证据源于3项临床研究及一项Meta分析[7-10]。但三项对新辅助化疗在局部晚期鼻咽癌患者预后影响的临床研究中均对局部晚期鼻咽癌入组分期提出要求。Sun等[7]入组标准为Ⅲ~ⅣB期，除外T3~4N0M0患者，Cao等[8]入组标准则为Ⅲ~ⅣB期，除外T3N0~1M0期。Lee等[9]入组标准为Ⅲ~ⅣB期。三组研究均同时去除了Ⅱ期即T2N0-1M0、T1N1M0低危转移患者。Chen等[11]Meta分析纳入9项研究共1 988例鼻咽癌患者，结果提示新辅助化疗+同期放化疗相比单纯同期放化疗可降低远处转移率（P=0.03）。笔者认为基于鼻咽癌复发转移模式的不同，即局部晚期T分期（T3~4）早N分期（N0~1）组患者更倾向局部治疗失败，而晚N分期（N2~3）早T分期（T1~2）患者更倾向出现远处转移，基于新辅助化疗对远处转移的控制，笔者认为新辅助化疗更适用于高危转移即晚N分期（N2~3）早T分期（T1~2）患者。
研究发现T、N分期对患者预后影响并不相同，相较T分期，N分期是影响远处转移、总生存的主要因素[4-5, 12-14]。Setakornnukul等[12]266例局部晚期鼻咽癌行NCT-CCRT及同期放化疗+辅助化疗的回顾分析发现N3患者在NCT中明显获益，远处转移危险系数较辅助化疗者为0.48。Chen等[15] 556例T3~4N0~3鼻咽癌患者，经单纯放疗，结果发现N0、N1、N2、N3的5年OS分别为73.98%、65.96%、57.58%、29.39%（P=0.0009），T、N分期均是影响总生存、远处转移的独立预后因素，但N分期是主要预后指标，T分期为次要相关因素。在目前IMRT放射治疗背景下，鼻咽癌局控率得到明显提高，本组仅复发7例，5年无局部复发率为97.7%，因此对局部晚期鼻咽癌依据N分期进行分层治疗较为合适。例如对高危转移的N2~3期患者行高强度诱导化疗+同期放化疗，低危患者行同期放化疗或2程诱导后同期放化疗等。
单纯对N2~3期局部晚期鼻咽癌的研究较少。Yin等[16]比较了不同同期化疗强度的128例N2~3期鼻咽癌患者预后，结果提示N2~3期鼻咽癌患者在同期放化疗中提高化疗强度可提高总生存率，降低远处转移率。Kawahira等[17]小样本回顾分析N2~3期局部晚期鼻咽癌，12例行TPF3程诱导化疗，16例行同期放化疗+辅助治疗，结果显示TPF诱导化疗组明显提高患者总生存、降低远处转移率，两组3年OS分别为94%、75%，两组3年远处转移率分别为0、26%。魏嘉旺等[18]认为N2~3期局部晚期鼻咽癌为系统性疾病，在就诊前已有相当部分病例存在微转移灶，高强度的新辅助化疗可杀灭微转移灶，提高该部分患者的总生存、降低远处转移率，该研究按照1:2:1比例以年龄、N分期、病理类型、NCT方案配对后，NCT≥3程、NCT=2程、NCT=0程分别有179例、358例、179例N2~3期局部晚期鼻咽癌纳入研究，中位随访58月后，三组5年OS分别为89.4%、81.6%、73.7%（P=0.000），5年DFS分别为83.2%、69.8%、64.2%（P=0.001），5年DMFS分别为86.6%、76.0%、68.3%（P=0.000）。本研究结果同上述两项研究，均提示对N2~3期局部晚期鼻咽癌患者提高新辅助化疗药物强度或剂量强度可明显降低该部分患者远处转移率，提高总生存率。
本研究局部复发率较低，5年无局部复发率高达97.7%。大部分文献报道鼻咽癌放疗剂量GTV为68~72 Gy/30~32次[7, 19]。分析本组数据，有61例（22.6%）行75~80 Gy的剂量，提示较高的放疗剂量可进一步提高局部控制率，但伴随高剂量放疗，放疗后遗症如放射线脑病、放射线中耳炎、放射线脊髓炎、激素分泌水平下降等可能进一步升高而严重影响患者生活质量。对高剂量放疗研究值得进一步探讨。
本研究提示年龄 < 50岁患者较易发生远处转移（P=0.009）。原因可能为：鼻咽癌为成人常见肿瘤，发病高峰年龄40~59岁，故在 < 50岁患者中发病可能预示肿瘤侵袭性较强，出现远处转移概率较高。有研究结果提示 > 50岁患者更易出现远处转移[3]（P=0.025），但该研究仅行2程新辅助化疗，是否对总生存造成影响进一步影响年龄因素并不确定。
因本文为回顾分析，存在较多局限性：（1）样本量较少，全组仅270例，N3病例仅35例（13%）；（2）病例存在一定程度选择偏倚。临床行3程及以上诱导化疗者多身体状态较好，医师评估可耐受化疗的患者；（3）本研究新辅助化疗方案多样，文献报道奈达铂在同期化疗中与顺铂同效果，但在诱导化疗中疗效是否相同并无文献报道[19]。本研究诱导化疗中将奈达铂与顺铂合并一组统计，可能对结果造成一定影响。
综上，N2~3期局部晚期鼻咽癌患者行NCT≥3程诱导化疗+同步放化疗可明显提高总生存、降低远处转移率。对局部晚期鼻咽癌分层治疗的前瞻性临床研究亟待探索。
作者贡献吕丽：文献采集，论文撰写林劼：论文设计，论文修改和审阅 -
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