胆道恶性肿瘤的免疫治疗现状及研究进展

Immunotherapy for biliary tract cancer： Current status and research advances

摘要

胆道恶性肿瘤（BTC）是一种高度恶性、预后较差的消化道肿瘤，其有限的治疗手段和复杂的肿瘤微环境构成了临床治疗的主要挑战。本文系统梳理BTC免疫微环境的基本特征，进一步综述了免疫检查点抑制剂在BTC治疗中的作用，同时探讨癌症疫苗和过继性细胞免疫疗法等前沿策略。尽管BTC的高度异质性与免疫抑制微环境仍是制约疗效提升的主要障碍，未来基于多组学的生物标志物体系构建、新型联合策略的探索以及对免疫微环境的深度调控有望改善BTC患者的预后。

Abstract

Biliary tract cancer （BTC） is a highly malignant gastrointestinal tumor with a poor prognosis， and its limited treatment options and complex tumor microenvironment have posed significant challenges in clinical treatment. This article systematically describes the fundamental features of the immunosupressive microenvironment in BTC and reviews the role of immune checkpoint inhibitors in the treatment of BTC， as well as the emerging strategies such as cancer vaccines and adoptive cell transfer therapy. Although the improvement in treatment outcome is limited by high tumor heterogeneity and the immunosuppressive microenvironment， it is expected to improve the prognosis of BTC patients by constructing a biomarker system based on multi-omics， exploring novel combined treatment strategies， and deeply regulating the tumor microenvironment.

关键词

胆道肿瘤 / 免疫疗法 / 治疗学

Key words

Biliary Tract Neoplasms / Immunotherapy / Therapeutics

胆道恶性肿瘤（biliary tract cancer，BTC）是一种起源于胆管上皮、具有高度异质性的恶性肿瘤，由不同的病理类型组成，包括胆管癌（cholangiocarcinoma，CCA）和胆囊癌（gallbladder cancer，GBC）^［1］。CCA的发病率在全球范围内不断上升，目前约占原发性肝癌的15%^［2］；GBC恶性程度高，预后差，我国GBC相关的死亡人数占全球的28%^［3］，这表明BTC已成为一个不可忽视的公共卫生问题。

手术切除是早期BTC的唯一根治手段，但超过半数患者确诊时已失去手术机会，晚期BTC患者的治疗选择十分有限^［4］。近年来，免疫治疗取得了突破性进展。Ⅲ期临床试验TOPAZ-1和KEYNOTE-966证实，在吉西他滨和顺铂（GC）方案基础上联合程序性死亡配体1（programmed death-ligand 1，PD-L1）抑制剂度伐利尤单抗或程序性死亡受体1（programmed death-1，PD-1）抑制剂帕博利珠单抗，能够显著改善患者生存，标志着BTC治疗进入了免疫联合化疗的新时代^［5-6］。本综述旨在系统阐述BTC免疫治疗的现状，并展望其未来研究方向。

1 BTC的免疫微环境

绝大多数BTC在免疫学上被归类为“冷肿瘤”，其肿瘤微环境具有高度的免疫抑制性与复杂性，在促肿瘤炎症发生的同时介导免疫逃逸^［7-9］。免疫抑制性细胞群体在BTC的免疫微环境中占据主导地位，其富含髓系细胞，包括髓源性抑制细胞（myeloid-derived suppressor cell，MDSC）、肿瘤相关巨噬细胞（tumor-associated macrophages，TAM）和肿瘤相关中性粒细胞（tumor-associated neutrophils，TAN）^［10］。此外，耗竭型CD8⁺T细胞在BTC微环境中显著扩增，其特征性表达多种免疫检查点基因如TIGIT，靶向TIGIT可阻断其介导的免疫抑制性细胞互作^［11］。肿瘤相关成纤维细胞是BTC微环境中主要的间质细胞类型，通过分泌细胞外基质蛋白构建典型的纤维化环境，为BTC提供免疫屏障^［12］。

机制研究进一步揭示了微环境中各组分的动态调控关系。研究表明，CCA中TAM是PD-L1的主要来源，单一靶向TAM会引发粒细胞样MDSC（G-MDSC）的代偿性聚集进而产生治疗抵抗；而同时靶向TAM和G-MDSC可显著增强PD-1抑制剂的疗效^［13］。靶向CTLA-4联合GC方案同样可提高PD-1抑制剂的治疗响应，机制在于三联疗法可募集并活化CXCR3⁺CD8⁺T细胞，同时减少单核样MDSC（M-MDSC）的免疫抑制功能^［14］。He等^［15］发现PD-1抑制后可代偿性激活TIM3通路，导致免疫逃逸；同时靶向PD-1和TIM3有望恢复CD8⁺T细胞的抗肿瘤活性。

综上所述，多种免疫细胞与间质细胞之间错综复杂的相互作用，共同构筑了BTC的免疫抑制微环境，靶向多种免疫抑制细胞与免疫检查点的多靶点联合方案有望逆转免疫抑制，实现BTC从“冷肿瘤”向“热肿瘤”的转化。

2 BTC免疫治疗响应相关生物标志物

目前尚无单一可靠的生物标志物被纳入BTC的常规临床管理，但研究揭示了多个潜在的预测因子（表1）。

2.1 错配修复缺陷（defective mismatch repair，dMMR）和微卫星不稳定（microsatellite instability，MSI）

约5%的BTC存在dMMR，从而导致微卫星高度不稳定（MSI-H）表型^［22］。MSI/dMMR的BTC因DNA修复缺陷导致移码突变，产生大量新抗原，激活强效的抗肿瘤免疫反应，使得此类肿瘤对免疫检查点抑制剂（immune checkpoint inhibitor，ICI）的响应率显著高于错配修复功能完整（proficient mismatch repair，pMMR）的肿瘤^［23］。多项临床试验证实MSI/dMMR的BTC患者可显著获益于ICI^［16-18］，基于这些卓越数据，dMMR/MSI-H已成为目前BTC中预测ICI疗效最明确的生物标志物。然而，由于其发生率较低，仅能使少数患者获益。

2.2 肿瘤突变负荷（tumor mutation burden，TMB）

TMB是另一个潜在的预测指标。研究表明，高MSI肿瘤有82.1%同时表现为高TMB，但高TMB肿瘤仅有18.3%同时伴随高MSI，说明存在大量微卫星稳定但TMB高的肿瘤群体^［24］。Lin等^［19］对803例中国BTC患者进行的基因组分析揭示了中西方BTC人群的基因突变谱差异，不同于西方人群，中国队列中最常改变的BTC相关基因包括 TP53（53%）、KRAS（26%）、ARID1A（18%）、LRP1B（14%）和CDKN2A（14%）。另一项研究显示，TMB水平高低与PFS无关，但高TMB与更高的客观缓解率（objective response rate，ORR）相关^［20］。上述研究提示TMB可作为潜在生物标志物，以筛选免疫治疗获益的患者。

2.3 PD-L1表达

尽管PD-L1表达是其他癌症中常用的免疫治疗生物标志物，但在BTC中其预测价值仍未明确。在TOPAZ-1试验中，无论肿瘤细胞PD-L1表达水平如何，患者从伐利尤单抗联合化疗中的生存获益相似^［5］。KEYNOTE-966试验也报告了PD-L1表达水平的预测价值有限^［6］。然而，在KEYNOTE-028试验中，PD-L1的表达水平与BTC患者接受帕博利珠单抗治疗的临床效果呈正相关^［21］。这些矛盾的发现可能与其高度异质性、PD-L1检测抗体、判读标准的不同相关。因此，将PD-L1作为预测BTC免疫治疗响应的独立生物标志物具有局限性，仍需更多的研究验证。

3 BTC当前的免疫治疗策略（表2）

3.1 ICI

3.1.1 ICI单药治疗

ICI单药治疗是BTC免疫治疗的基础方案。Ⅱ期试验KEYNOTE-158和Ⅰb期试验KEYNOTE-028评估了PD-1抑制剂帕博利珠单抗治疗晚期BTC患者的安全性与有效性，并表明帕博利珠单抗的治疗相关不良事件发生率低于20%^［25］。另一项研究展示了晚期难治性BTC患者使用PD-L1抑制剂度伐利尤单抗后的生存获益^［26］。以上研究表明，PD-1/PD-L1抑制剂对BTC有一定的治疗效果，尽管效果未超过一线化疗方案，但其可控的安全性与耐受性为后续的联合治疗奠定了基础。

3.1.2 ICI联合化疗

ICI联合GC方案已成为晚期BTC一线治疗的新标准，这一地位由两项大型Ⅲ期临床试验共同确立，两项试验表明ICI联合GC方案可以显著提高BTC患者的生存获益^［5-6］。TOPAZ-1研究的长期随访更显示，联合组的24个月总生存率是化疗组的2倍（23.6% vs 11.5%），且未显著增加3级及以上不良事件发生率，提示ICI联合化疗在改善患者长期预后方面具有显著优势^［39］。此外，多项Ⅱ期研究也报告了令人鼓舞的疗效和可控的安全性^［27-28］。这些证据共同确立了免疫联合化疗作为晚期BTC一线治疗的基石地位。

3.1.3 ICI联合靶向治疗

血管生成是肿瘤发生发展过程中关键的病理生理环节^［40］，靶向药物通过阻断血管内皮生长因子受体及成纤维细胞生长因子受体可以抑制血管形成^［41］。同时靶向药物可抑制促血管生成相关的酪氨酸激酶活性，并通过调节免疫微环境促进ICI的治疗效果^［42］。一项Ⅱ期临床研究仅评估ICI联合仑伐替尼的治疗效果，结果显示联合方案具有良好前景^［29］。一项单臂开放的Ⅱ期临床试验（REGOMUNE）显示，尽管未达终点，联合方案在29例可评估疗效的患者中已显示出抗肿瘤活性，4例患者部分缓解，11例患者疾病稳定^［30］。另一项多中心Ⅱ期临床试验也证实ICI联合靶向治疗具有一定的有效性与安全性^［31］。这些方案为晚期BTC治疗提供了有希望的选择，但其疗效仍需Ⅲ期试验确认。

3.1.4 ICI联合其他治疗方案

ICI联合其他治疗方案仍在探索。双免疫检查点抑制疗法，如纳武利尤单抗联合伊匹木单抗，一项试验队列显示其ORR为23%，疾病控制率（disease control rate，DCR）达到44%，疗效优于单药^［32］。目前的研究表明，局部放疗与免疫疗法联用时可产生协同效应，提升全身抗肿瘤免疫，甚至诱发未照射病灶的缩小，也就是“远隔效应”^［43］。替西木单抗联合微波消融的结果显示，治疗后患者血液循环中活化的CD8⁺T细胞数量增加，T细胞克隆重排多样性有增加趋势，表明全身免疫激活，提示了远端效应的潜在机制^［33］。樊嘉院士主导的ZSAB-TOP研究取得了突破性成果，使用PD-1抑制剂替雷利珠单抗、TIGIT抑制剂欧司珀利单抗联合GC方案作为治疗方案，在45例晚期BTC患者中确认的ORR高达51.2%，DCR为82.9%，且安全性可控^［34］。这为超越传统“化疗+单免疫”模式提供了新范式^［34］。

3.2 癌症疫苗

癌症疫苗接种是通过引入一种或多种肿瘤抗原，以诱导机体产生特异性免疫应答的治疗方法，旨在增强免疫系统对癌细胞的识别与清除能力。根据所使用的抗原种类，通常可分为3类：基于细胞的肿瘤抗原递送、肿瘤抗原蛋白以及编码肿瘤抗原的遗传物质^［44］。一项Ⅰ期临床试验表明，一种针对CDCA1、CDH3、KIF20A的多肽疫苗可以成功诱导晚期BTC患者的特异性T细胞免疫反应，可使55.6%的患者达到病情稳定^［35］。虽然单一疫苗的治疗效果有限，但一项术后联合免疫疗法的结果显示，联合方案可提高术后BTC患者的生存预期，展示肿瘤疫苗联合疗法的治疗潜力^［36］。在靶点发掘方面，Tang等^［45］筛选出3个mRNA疫苗的理想靶点，分别为TRRAP、FCGR1A、CD247，并预测“冷肿瘤”的免疫系统可被疫苗唤醒，使难以响应免疫治疗的患者获益。在GBC方面，整合基因组显示ELF3、TP53和ERBB2可作为潜在的疫苗靶点，预示着GBC的个性化疫苗具有发展前景^［46］。目前该领域仍处于早期探索阶段，个性化mRNA疫苗及联合策略是未来的重要方向。

3.3 过继性免疫细胞疗法（adoptive cell transfer therapy，ACT）

ACT通过体外改造和扩增肿瘤特异性T细胞，将其回输至患者体内，以实现对肿瘤的靶向杀伤。尽管CAR-T疗法在血液肿瘤治疗中已取得显著成效，但在BTC等实体瘤治疗中仍面临肿瘤异质性、T细胞浸润不足和免疫抑制微环境复杂等多重挑战^［47］。

研究显示，对1例携带ERBB2突变的转移性CCA患者，回输体外扩增的突变特异性Th1细胞后，其肿瘤出现了显著消退并长期维持^［48］。一项Ⅰ期临床试验显示，CART-EGFR细胞回输后患者总体耐受性良好，且有一定的治疗效果^［37］。在HER2阳性实体瘤的Ⅰ期临床试验中，CART-HER2细胞的有效性同样得到证明^［38］。目前抗MUC-1和CD133的CAR-T疗法已在体外研究显示疗效^［49-50］，需进一步验证；针对不可切除胰腺或BTC中的CD19的CAR-T疗法（NCT06196658）和针对iCCA中的MUC-1的CAR-T疗法（NCT03633773）正在进行中。总而言之，ACT应用于晚期BTC的有效性和安全性仍需更多的基础研究和大规模临床试验来证实。

4 小结与展望

BTC的免疫治疗已从早期的探索阶段迈入了临床实践，以TOPAZ-1和KEYNOTE-966研究为代表的化疗联合免疫治疗方案成功改写了晚期BTC的一线治疗标准，为患者带来了确切的生存获益。然而，BTC高度的异质性和复杂的免疫抑制微环境决定了其免疫治疗仍面临巨大挑战。未来BTC治疗的关键方向在于构建多组学驱动的精准生物标志物体系以优化患者分层，开发新型免疫联合策略以克服治疗抵抗，通过靶向免疫抑制微环境实现“冷热转化”，并推动个体化疫苗及下一代细胞疗法等前沿突破。

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基金资助

上海市浦东新区卫健委重点学科建设项目(PWZxk2022-02)

上海市浦东新区卫健委卫生计生科技青年科技项目(PW2022B-07)

国家自然科学基金面上项目(82472875)