Research progress of targeted therapy for cervical cancer by tumor-associated macrophages
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摘要: 肿瘤相关巨噬细胞（TAMs）是肿瘤微环境（TME）中重要的免疫细胞，可分泌多种细胞因子参与和调控宫颈癌（CC）的生物学行为。详细了解TAM影响CC的生长和转移机制，是研发靶向治疗药物的关键。本文就近年来对TAM在CC中的治疗进展进行综述，重点探讨TAM靶向治疗CC的潜在治疗靶点、疫苗及药物，为CC新型靶向药物的研发提供理论依据，以期改善患者生存质量和延长其生存时间。Abstract: Tumor associated macrophages (TAM) are important immune cells in the tumor microenvironment (TME), which can secrete a variety of cytokines to participate in and regulate the biological behavior of cervical cancer (CC). A detailed understanding of the mechanism of TAM affecting the growth and metastasis of CC is the key to the development of targeted therapies. In this paper, the progress of TAM treatment in CC was reviewed in recent years, and the potential therapeutic targets, vaccines and drugs for TAM targeted treatment of CC were mainly discussed, which may provide theoretical basis for the research and development of novel targeted drugs for CC, in order to improve the quality of life and prolong the survival time of patients.
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Keywords:
- cervical cancer /
- tumor-associated macrophages /
- immunotherapy /
- phenotypic transformation /
- vaccine
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慢性心力衰竭是各种心脏疾病的终末阶段，其发病率、病死率及再住院率较高，严重影响患者的生存质量[1]。射血分数降低的心力衰竭(HFrEF)患者的心功能及预后更差[2]。应用血管紧张素转换酶(ACE)抑制剂治疗HFrEF已被临床公认，而血管紧张素受体阻滞剂(ARBs)是一种安全可靠的替代药物[3]。血管紧张素受体脑啡肽酶抑制剂(ARNI)[4-6]可作用于肾素-血管紧张素-醛固酮系统(RAAS)和中性内肽酶系统。MCMURRAY J J等[7]研究发现，沙库巴曲缬沙坦组HFrEF患者心力衰竭住院率和死亡率低于依那普利组。利钠肽可抑制肾素和醛固酮的分泌，选择性阻断血管紧张素Ⅱ的1型(AT1)受体，进而减少血管收缩、水钠潴留，延缓心肌肥厚[8]。目前，关于沙库巴曲缬沙坦对超声心动图参数及左室重构的影响的数据很少[9-10]。本研究评估沙库巴曲缬沙坦对HFrEF患者超声参数及左室重构的影响，现报告如下。
1. 资料与方法
1.1 一般资料
选取2018年7月—2020年12月在苏州市第九人民医院心内科住院治疗的50例慢性HFrEF患者为研究对象。纳入标准: ①年龄≥18岁者; ②纽约心脏病协会(NYHA)分级Ⅱ~Ⅳ级者; ③射血分数 < 40%者; ④患者在入组前12个月内因心力衰竭住院; ⑤未服用任何ACE抑制剂或ARB的患者; ⑥服用稳定剂量β-受体阻滞剂、ACE抑制剂或ARB至少4周的患者; ⑦签署知情同意书者。排除标准: ①症状性低血压、收缩压 < 100.0 mmHg者; ②估计肾小球滤过率(eGFR) < 30.0 mL/(min·1.73 m2)者; ③筛查时血清钾水平>5.2 mmol/L者; ④血管性水肿病史者; ⑤ ACE抑制剂或ARB治疗下出现副作用者; ⑥可纠正的瓣膜病者; ⑦ 3个月内急性冠状动脉综合征者; ⑧ 3个月内冠状动脉血管重建术者。基于既往研究[10-12]结果，左室射血分数(LVEF)改善>5%定义为对沙库巴曲缬沙坦有显著反应。
1.2 研究步骤
为了将ACE和脑啡肽酶抑制作用引起的血管性水肿的风险降至最低，在开始使用沙库巴曲缬沙坦之前，停用ACE抑制剂至少36 h。禁止使用ACE抑制剂或ARB与沙库巴曲缬沙坦联合治疗，患者在开始使用沙库巴曲缬沙坦前需接受临床检查以及超声心动图和彩色多普勒超声评估，在3个月时重复相同的检查，采用NYHA分级进行心功能评价。
1.3 超声心动图评估
超声心动图检查由1名对患者状态设盲的超声科医师实施，常规超声心动图检查在患者使用沙库巴曲缬沙坦治疗前24~72 h进行，并在沙库巴曲缬沙坦治疗后3个月时重复评估[13]。
1.3.1 左心室彩色多普勒超声评估
在左心室二维超声心动图成像上评价左室收缩功能，使用M模式在乳头肌水平测量胸骨旁长轴视图下左室舒张末期内径(LVEDD)以及左室收缩末期内径(LVESD), 然后用双平面法测量左室收缩末期容积(LVESV)、左室舒张末期容积(LVEDV)。评估E波和A波的峰值，计算E/A比值和E波减速时间。离线彩色编码组织多普勒成像使用心尖四腔视图，将样本置于二尖瓣间隔和外侧二尖瓣环上，计算舒张早期速度(E′)和舒张末期速度(A′)。计算二尖瓣间隔和二尖瓣外侧环的平均E′速度，计算E/E′比值。根据指南对每个患者的左室舒张功能不全进行分级，在心尖四腔和二腔测量LA最大容积指数(mL/m2), 用传统的超声心动图标记评估二尖瓣反流。
1.3.2 右心室彩色多普勒超声评估
应用二维心尖四腔视图观察右心室的容积和收缩力，计算右心室面积变化百分比。从三尖瓣瓣环沿游离壁描记心内膜心肌轮廓至心尖部，然后沿室间隔描记回瓣环。采用M型图像获得三尖瓣环平面收缩偏移(TAPSE)。将M型光标定位在三尖瓣平面与右室游离壁的交界处，计算三尖瓣环从舒张末期到收缩末期的总位移。评价右心室功能指数(MPI), 检测三尖瓣关闭开放时间(TCO), 包括等容收缩时间、射血时间(ET)和等容舒张时间。评估纵向偏移速度(S′), S′ < 10 cm/s是定义RV功能异常的临界值，使用简化的Bernoulli方程[11]测量收缩期间右心室与右心房之间的压力梯度。
1.4 统计学分析
采用SPSS 21.0软件进行数据分析，所有临床变量在纳入时进行评估，在沙库巴曲缬沙坦开始使用前，由1名对患者状态设盲的高年资超声科医师评估超声参数，并在治疗3个月后重复进行。连续变量用平均值(标准差或四分位数表示，使用非配对Student′s t检验或Mann-Whitney检验对患者组之间的连续变量进行比较，分类变量用卡方检验或Fisher精确检验进行比较, P < 0.05为差异有统计学意义。
2. 结果
2.1 患者人口学资料
本研究最初纳入50例患者，研究期间7例不耐受沙库巴曲缬沙坦治疗而被剔除，最终完成研究的患者43例。43例患者年龄(70.0±10.0)岁，女12例，男31例; 合并高血压25例，合并糖尿病15例; 有吸烟史8例，高胆固醇血症21例; 特发性心力衰竭18例，缺血性心力衰竭25例; NYHA分级Ⅱ级15例, Ⅲ级28例; 32例沙库巴曲缬沙坦最大剂量200 mg/d, 11例沙库巴曲缬沙坦平均剂量100 mg/d。
2.2 沙库巴曲缬沙坦治疗前后的超声参数比较
43例患者治疗前后的LVEF、LVESV、LVEDD、速度时间分积(IVT)、右室收缩压比较，差异均有统计学意义(P < 0.01)。见表 1。
表 1 43例患者沙库巴曲缬沙坦治疗前后超声参数比较(x±s)指标 治疗前 治疗后 LVEF/% 32.6±5.3 36.2±6.5** LVEDV/mL 172.7±50.0 166.0±58.8 LVESV/mL 117.6±41.5 108.9±46.1** LVEDD/mm 60.3±5.4 57.1±5.7** LVESD/mm 49.1±7.4 48.5±6.5 IVT/cm2 16.5±0.3 17.8±0.8** E/A 1.1±0.6 1.0±0.5 心脏指数/[L/(min·m2)] 2.3±0.3 2.4±0.4 右室收缩压/mmHg 39.1±10.4 32.5±8.4** RVEDD/mm 31.3±4.5 31.0±4.6 BDRV直径/mm 41.2±6.5 41.6±6.2 TAPSE/mm 18.0±4.0 18.4±4.5 RVFS/% 36.6±6.2 38.0±6.2 LVEF: 左室射血分数; LVEDV: 左室舒张末期容积;
LVESV: 左室收缩末期容积; LVEDD: 左室舒张末期内径;
LVESD: 左室收缩末期内径; IVT: 速度时间分积;
E/A: E峰与A峰比值; RVEDD: 右室舒张末期内径;
BDRV: 基础右室内径; TAPSE: 三尖瓣环平面收缩偏移;
RVFS: 右室缩短分数。与治疗前比较, **P < 0.01。2.3 不同超声反应患者资料比较
沙库巴曲缬沙坦治疗后超声有反应者19例，表现为较轻的左室重构，超声无反应者24例。有反应组与无反应组LVEDV、LVESV、LVEDD、二尖瓣反流比率比较，差异均有统计学意义(P < 0.05或P < 0.01)。沙库巴曲缬沙坦反应对左室舒张功能或右室参数无影响。见表 2。
表 2 沙库巴曲缬沙坦超声有反应组与无反应组相关参数比较(x±s)[n(%)]指标 有反应组(n=19) 无反应组(n=24) 年龄/岁 72.0±11.0 69.0±10.0 女性 7(36.8) 5(20.8) LVEF/% 34.6±4.7 36.0±2.7 LVEDV/mL 144.0±37.9 193.3±48.7** LVESV/mL 96.6±28.0 133.1±42.8** LVEDD/mm 57.5±5.0 61.4±4.2** LVESD/mm 48.8±5.6 50.2±9.6 IVT/cm2 16.2±4.2 17.4±3.5 E/A 1.2±0.7 1.0±0.6 心脏指数/[L/(min·m2)] 2.4±0.5 2.3±0.4 右室收缩压/mmHg 36.6±8.5 41.5±11.4 RVEDD/mm 30.5±4.0 31.1±4.5 BDRV直径/mm 41.5±6.0 41.1±5.6 TAPSE/mm 19.3±3.6 17.5±4.0 二尖瓣反流 6(31.6) 17(70.8)* 与有反应组比较, *P < 0.05, **P < 0.01。 2.4 沙库巴曲缬沙坦不耐受原因
本研究剔除的7例不耐受沙库巴曲缬沙坦治疗患者的血清肌酐水平为(136.0±99.0) μmol/L, 高于43例正常接受沙库巴曲缬沙坦治疗患者的(103.0±25.0) μmol/L, 差异有统计学意义(P=0.03)。右室超声参数、心力衰竭病因不影响沙库巴曲缬沙坦的反应或耐受性。
3. 讨论
2015年，美国食品药品监督管理局(FDA)批准沙库巴曲缬沙坦可用于慢性心力衰竭患者的治疗。随着循证医学数据的积累, 2017年美国心力衰竭指南[14]推荐LVEF < 40%的心力衰竭患者可使用LCZ696[单一物质中结合缬沙坦(ARB)和沙库巴曲(脑啡肽酶抑制剂)的分子]治疗，推荐心功能Ⅱ~Ⅲ级、可以耐受ACEI/ARB治疗的HFrEF患者采用LCZ696治疗。尽管沙库巴曲缬沙坦可显著降低HFrEF患者的发病率和死亡率，但有关其影响左室重塑及相应心脏超声心动图变化的研究仍较少见。本研究表明，沙库巴曲缬沙坦对曾接受ACE抑制剂治疗的HFrEF患者的左室重构和右室收缩压有额外的作用，沙库巴曲缬沙坦有反应者表现出较轻的左室重构和较低的二尖瓣反流发生率。
血管紧张素受体-脑啡肽酶抑制剂复合物是治疗HFrEF患者的一类新型药物。脑啡肽酶是一种膜结合内肽酶，可水解心房利钠肽、脑利钠肽和C型利钠肽以及其他内源性血管舒张肽[15], 抑制脑啡肽酶能够升高利钠肽水平，从而获得利钠肽效应和血管扩张等潜在益处[16]。沙库巴曲缬沙坦双重抑制RAAS和脑啡肽酶系统，能减轻血管紧张素Ⅱ介导的心肌细胞纤维化，发挥抗增殖和抗肥厚的作用[15-16]。既往研究[17]曾对ACE和脑啡肽酶抑制剂联合用药进行了试验，但由于缓激肽水平异常增加导致的血管性水肿的发生风险升高，所以药物试验被中止。目前，沙库巴曲缬沙坦对结构重塑的作用尚未得到充分证实，而事实上左室重构是HFrEF患者疾病进展的潜在主要机制[18]。最近一项前瞻性随机研究[9]表明，血管紧张素受体脑啡肽酶抑制剂比ARBs可更有效地改善心力衰竭相关的二尖瓣反流。作者发现，与缬沙坦相比，沙库巴曲缬沙坦可进一步缩小有效反流口面积，降低左室舒张末期容积指数、左房容积指数和二尖瓣血流速度与二尖瓣环舒张速度比值(E/E′)。一项回顾性研究[10]也发现，接受沙库巴曲缬沙坦3个月中位治疗时间的患者的LVEF、左室收缩末期内径、左室舒张末期内径及左室质量指数有明显改善。本研究采用前瞻性设计评估沙库巴曲缬沙坦对左室重构的影响，结果表明，沙库巴曲缬沙坦能够对左室结构重塑带来获益。
沙库巴曲缬沙坦起初被特定用于HFrEF患者治疗，预期研究成果及效应的评估可基于临床指标和超声心动图标准。虽然研究纳入了临床基本资料，如年龄、种族、合并症以及较低剂量用药，但这些因素对沙库巴曲缬沙坦的总体效果没有产生影响[19]。本研究尝试进一步确定影响左室射血分数改善的临床或超声因素。基于既往研究[10-12], LVEF绝对改善>5%被认为有临床意义，定义为沙库巴曲缬沙坦有反应。本研究发现，与无反应者相比，沙库巴曲缬沙坦超声有反应者表现出较低的LVEDV、LVESV, 反映出较轻的左室重构; 与无反应者相比，沙库巴曲缬沙坦有反应者二尖瓣反流比率更低，未发现左室舒张功能或右室参数影响沙库巴曲缬沙坦反应。目前，沙库巴曲缬沙坦对超声左室重塑影响的研究仅有一项前瞻性研究[20]。本研究发现，使用LCZ696时，即使已经使用ACE抑制剂治疗的患者, LVEF也有望得到显著改善。因此，沙库巴曲缬沙坦对左室重构的改善可能是由于抑制脑啡肽酶的额外作用，抑制脑啡肽酶升高利钠肽的这种补充作用改善了左心室功能。
综上所述，在HFrEF患者中，沙库巴曲缬沙坦可显著改善左室收缩重构，对左室舒张功能或右室超声参数无显著影响。沙库巴曲缬沙坦有反应者表现出较轻的左室重构和较低的二尖瓣反流比率。因此，沙库巴曲缬沙坦可在早期用于HFrEF患者的治疗，以进一步限制左室重构。
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