Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Laboratory Animal Center, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
Med. 2023 Jun 9;4(6):373-393.e8. doi: 10.1016/j.medj.2023.04.008. Epub 2023 May 17.
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).
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.
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 CCR7CD8 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.
We uncovered a critical role of DC subsets in immunotherapy, which has implications for designing novel therapies and patient stratification strategies.
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.
树突状细胞（DC）广泛参与免疫微环境，这表明它们在癌症免疫治疗中有很大的潜力。了解患者群体中 DC 的多样性可能会增强免疫检查点抑制剂（ICI）的临床获益。
对两项临床试验的乳腺肿瘤进行单细胞分析，以研究 DC 的异质性。采用多组学、组织学特征分析和临床前实验来评估所鉴定的 DC 在肿瘤微环境中的作用。利用四项独立的临床试验来探索预测 ICI 和化疗结果的生物标志物。
我们鉴定了一种独特的 CCL19 表达功能状态的 DC，与对抗程序性死亡（配体）-1（PD-（L）1）的有利反应相关，其具有迁移和免疫调节表型。这些细胞与抗肿瘤 T 细胞免疫和三级淋巴结构和淋巴聚集物相关，定义了三阴性乳腺癌的免疫原性微环境。在体内，通过 Ccl19 基因敲除消除 CCL19 DC 会削弱抗 PD-1 治疗时的 CCR7+CD8+T 细胞和肿瘤消除。值得注意的是，高循环和肿瘤内 CCL19 水平与接受抗 PD-1 治疗但不是化疗的患者的更好反应和生存相关。
我们揭示了 DC 亚群在免疫治疗中的关键作用，这对设计新的治疗方法和患者分层策略具有重要意义。
本研究由中国国家重点研发计划、国家自然科学基金、上海市学术/技术带头人项目、上海市自然科学基金、上海市乳腺癌重点实验室、上海市医院发展中心（SHDC）和上海市卫生健康委员会资助。
