三阴性乳腺癌的雌激素受体、孕激素受体、人类表皮生长因子受体HER2均为阴性，对内分泌治疗和HER2靶向治疗无效，药物治疗主要依靠化疗。近年来，免疫细胞程序性死亡受体PD-1及其配体PD-L1的抑制剂对部分三阴性乳腺癌患者取得良好疗效。不过，这些免疫治疗药物非常昂贵，故有必要对其疗效进行精准预测。既往预测方法大多需要对肿瘤组织进行穿刺活检，不仅对患者创伤大，而且操作难、费用高、耗时长。循环肿瘤细胞等血液活检与肿瘤组织活检结果往往不一致，而且费用昂贵，针对三阴性乳腺癌免疫疗效预测也缺乏前瞻临床试验数据支持。 2023年5月17日，美国细胞出版社旗舰期刊《医学》在线发表复旦大学附属肿瘤医院吴松阳①、张思维①、马丁①、肖毅、刘引、陈力、宋效清、马晓燕、徐颖、柴文君、金希✉️、邵志敏✉️、江一舟✉️等学者的研究报告，首次发现趋化因子CCL19阳性树突状细胞可精准预测三阴性乳腺癌免疫疗效。 肿瘤微环境是肿瘤赖以生存的“土壤”，寻找其中的关键免疫细胞亚群，从而提高精准治疗效果，是乳腺癌免疫治疗研究的重要方向。树突状细胞属于白细胞，可发现病原体或肿瘤细胞，提交给T淋巴细胞杀灭，作为最重要的先天免疫细胞之一，在肿瘤微环境中发挥“侦察兵”的关键作用。但是，目前对于哪一类树突状细胞亚群最重要并可精准定向免疫治疗，仍然缺乏系统研究。 CCL19阳性树突状细胞是一群功能成熟的细胞亚群，具有高效的免疫调节能力，在具有该种细胞的肿瘤中，免疫杀伤能力处于高度激活状态。CCL19阳性树突状细胞对抗肿瘤免疫治疗发挥重要的“桥梁”作用，通过作用于抗肿瘤免疫的长期卫士记忆性T淋巴细胞，可发挥抗肿瘤与免疫治疗增敏作用。 多项独立临床试验证实，如果这种细胞高度浸润于肿瘤微环境，那么可以提示三阴性乳腺癌患者免疫治疗有效。体内实验发现，回输CCL19阳性树突状细胞可以活化CD8阳性T淋巴细胞功能，PD-1抑制剂疗效即可成倍增加，显著抑制肿瘤生长。 机制分析发现，该类树突状细胞通过关键功能分子趋化因子CCL19影响趋化因子受体CCR7阳性记忆性T淋巴细胞，进而与免疫治疗发挥协同作用，而联合使用CCL19与PD-1抑制剂可以进一步促进T淋巴细胞的肿瘤杀伤作用，激活三阴性乳腺癌抗肿瘤免疫。因此，基于CCL19的治疗方式可以作为提高三阴性乳腺癌免疫治疗疗效的潜在治疗策略。 该研究从肿瘤微环境视角出发，利用来自临床试验的一手数据，通过大样本配对的三阴性乳腺癌患者队列肿瘤新鲜组织、石蜡切片多重染色、外周血液样本分析等多种方法，完成多队列、多人种的综合分析，发现肿瘤内CCL19水平与外周血液循环CCL19水平明显正相关，通过国内外多项临床试验验证，研究者发现不仅肿瘤内CCL19水平与免疫治疗疗效相关，外周血液CCL19水平同样可以预测免疫治疗疗效。对于晚期三阴性乳腺癌，外周血液CCL19高的患者有80%能获得超过30%的肿瘤退缩，而CCL19低的患者获得明显肿瘤退缩的比例不足35%。 进一步研究证实，有针对性制定的免疫治疗无创检测方案CCL19水平检测，仅需要抽取1毫升血液，经过半小时分析，就能出具报告，有望指导三阴性乳腺癌患者免疫治疗更精准实施。通过酶联免疫吸附检测外周血液CCL19，有望实现免疫治疗患者的无创监测，做到疗效动态预测，及时调整治疗方案，改善患者预后。目前，相关研究已经申请发明专利。 该研究得到美国细胞出版社旗舰期刊《医学》审稿人高度评价，被认为具有很强的创新性与非常重要的临床应用价值，并将于2023年6月9日作为该期刊封面文章正式发表。2022年，该研究还入选第45届圣安东尼奥乳腺癌大会亮点讨论，该会议是全球规模最大、水平最高、影响力最强的国际乳腺癌学术会议。 江一舟研究员表示，当前肿瘤诊断及疗效检测主要依赖创伤性组织活检，不仅对患者创伤大，而且耗时长、价格高昂。通过外周血液等采集相关信息的无创液体活检，可以实现简便、无创、快速、低成本，克服了既往标志物预测效能不够高、需要有创组织活检两大痛点，有望在有效提升三阴性乳腺癌治疗效果的同时，减轻患者的医疗经济负担。 据悉，既往基于三阴性乳腺癌“复旦分型”的FUTURE-C-Plus临床试验，利用基础研究发现的靶点，通过一线双靶三联精准免疫治疗方案将晚期三阴性乳腺癌患者一线治疗的有效率提高至目前国际最高的81.3%，实现了从基础到临床的全链条“闭环”。本研究基于肿瘤微环境关键细胞亚群，将为乳腺癌免疫治疗再添新火，助力“复旦成果”制定“中国方案”，进一步指导三阴性乳腺癌精准免疫治疗的临床实践。Med. 2023 May 17. Impact Score: 20.28CCL19+ dendritic cells potentiate clinical benefit of anti-PD-(L)1 immunotherapy in triple-negative breast cancer.Song-Yang Wu, Si-Wei Zhang, Ding Ma, Yi Xiao, Yin Liu, Li Chen, Xiao-Qing Song, Xiao-Yan Ma, Ying Xu, Wen-Jun Chai, Xi Jin, Zhi-Ming Shao, Yi-Zhou Jiang.Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China.- Single-cell profiling of DCs in breast tumors from retrospective clinical trials
- CCL19+ DCs are associated with TLS/LA presence and ICI-responsive immune contexture
- DC-derived CCL19 mediates CCR7+CD8+ T cells to synergize with PD-1 blockade in TNBC
- Circulating and intratumoral CCL19 predicts improved clinical benefit of PD-1 blockade
Dendritic cells are essential for priming immune response against cancer. However, there is limited information on the clinical relevance between dendritic cell heterogeneity and immunotherapy response in breast cancer. Here, the authors leveraged retrospective clinical trials and identified a CCL19+ dendritic cell population associated with favorable responses to anti-PD-(L)1 immunotherapy, which indicated immunogenic contexture in triple-negative breast cancer. Mechanistically, dendritic cell-derived CCL19 synergized with anti-PD-1 to augment CD8+ T cell immunity. Corroborating human relevance, high circulating and intratumoral CCL19 was associated with superior response and survival in patients treated with PD-1 blockade but not with chemotherapy. Thus, the findings here may help design novel therapies and stratify patients most likely to benefit from immunotherapy using noninvasive liquid biopsy.BACKGROUND: The extensive involvement of dendritic cells (DCs) in immune contexture indicates their potent value in cancer immunotherapy. Understanding DC diversity in patient cohorts may strengthen the clinical benefit of immune checkpoint inhibitors (ICIs).METHODS: Single-cell profiling of breast tumors from two clinical trials was performed to investigate DC heterogeneity. Multiomics, tissue characterization, and pre-clinical experiments were used to evaluate the role of the identified DCs in the tumor microenvironment. Four independent clinical trials were leveraged to explore biomarkers to predict ICI and chemotherapy outcomes.FINDINGS: We identified a distinct CCL19-expressing functional state of DCs associated with favorable responses to anti-programmed death (ligand)-1 (PD-(L)1), which displayed migratory and immunomodulatory phenotypes. These cells were correlated with antitumor T cell immunity and the presence of tertiary lymphoid structures and lymphoid aggregates, defining immunogenic microenvironments in triple-negative breast cancer. In vivo, CCL19+ DC deletion by Ccl19 gene ablation dampened CCR7+CD8+ T cells and tumor elimination in response to anti-PD-1. Notably, high circulating and intratumoral CCL19 levels were associated with superior response and survival in patients receiving anti-PD-1 but not chemotherapy.CONCLUSIONS: We uncovered a critical role of DC subsets in immunotherapy, which has implications for designing novel therapies and patient stratification strategies.FUNDING: This study was funded by the National Key Research and Development Project of China, the National Natural Science Foundation of China, the Program of Shanghai Academic/Technology Research Leader, the Natural Science Foundation of Shanghai, the Shanghai Key Laboratory of Breast Cancer, the Shanghai Hospital Development Center (SHDC), and the Shanghai Health Commission.DOI: 10.1016/j.medj.2023.04.008
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