CCL19+ 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

doi:10.1016/j.medj.2023.04.008

CCL19⁺ dendritic cells potentiate clinical benefit of anti-PD-(L)1 immunotherapy in triple-negative breast cancer

Med. 2023 Jun 9;4(6):373-393.e8. doi: 10.1016/j.medj.2023.04.008. Epub 2023 May 17.

Authors

Song-Yang Wu¹, Si-Wei Zhang¹, Ding Ma¹, Yi Xiao¹, Yin Liu¹, Li Chen¹, Xiao-Qing Song¹, Xiao-Yan Ma¹, Ying Xu¹, Wen-Jun Chai², Xi Jin³, Zhi-Ming Shao⁴, Yi-Zhou Jiang⁵

Affiliations

¹ 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.
² Laboratory Animal Center, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
³ 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. Electronic address: 15111230037@fudan.edu.cn.
⁴ 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; Precision Cancer Medical Center, Fudan University Shanghai Cancer Center, Shanghai 201315, China. Electronic address: zhimingshao@fudan.edu.cn.
⁵ 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; Precision Cancer Medical Center, Fudan University Shanghai Cancer Center, Shanghai 201315, China. Electronic address: yizhoujiang@fudan.edu.cn.

PMID: 37201522
DOI: 10.1016/j.medj.2023.04.008

Abstract

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.

Keywords: Translation to patients.

MeSH terms

CD8-Positive T-Lymphocytes*
Chemokine CCL19 / metabolism
China
Dendritic Cells
Humans
Immunotherapy
Triple Negative Breast Neoplasms* / drug therapy
Tumor Microenvironment

Substances

CCL19 protein, human
Chemokine CCL19