Xing, Zhou, and Wang et al. demonstrated the role of CD103+CD8+ T cells in protection against breast cancer lung metastasis. Tumor antigen-specific CD103+CD8+ T cells were primed in TDLNs, and recruited to the lungs. Extracellular vehicles from early- and late-stage tumors differentially polarized alveolar macrophages to release CCL25 and IDO1, respectively. CCL25/CCR9 signaling recruited tumor antigen-specific CD103+CD8+ T cells to the lung, whereas IDO1 impaired pulmonary CD103+CD8+ T cells to facilitate lung metastasis. IDO1 inhibition increased CD103+CD8+ T cell infiltration in the lungs and alleviated lung metastasis.
Contributed by Shishir Pant
ABSTRACT: Tumor-antigen-specific CD8(+) T cells (CTLs) are the main effector immunocytes in anti-tumor immunity, but their systemic deployment against cancer metastasis remains uncharacterized. Here, we found that the abundance of tumor-specific CD103(+)CD8(+) T cells in the tumor-draining lymph nodes (TDLNs) was associated with improved lung-metastasis-free survival in breast cancer patients. In mouse cancer models, CD103(+)CD8(+) T cells were primed in TDLNs and recruited to the lungs via C-C motif chemokine ligand 5/receptor 9 (CCL25/CCR9) signaling to inhibit metastasis through antigen-specific immunity. Furthermore, extracellular vesicles (EVs) from early- and late-stage tumors differentially polarized alveolar macrophages to release CCL25 and IDO1, respectively, and the latter impaired pulmonary CD103(+)CD8(+) T cell deployment, facilitating lung metastasis. Depleting IDO1 effectively rescued CD103(+)CD8(+) T cell-mediated protection against lung metastasis. These findings exemplified long-range deployment of adaptive immunity to protect distant organs from metastasis, highlighting the therapeutic potential of reconstituting effector immune cell deployment (EICD) for cancer treatment.
Author Info: (1) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen
Author Info: (1) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (2) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (3) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (4) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (5) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (6) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (7) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (8) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (9) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (10) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (11) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (12) Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China. (13) School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. (14) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (15) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (16) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China; Zenith Institute of Medical Sciences, Guangzhou, China. Electronic address: songew@mail.sysu.edu.cn. (17) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. Electronic address: huangd63@mail.sysu.edu.cn.
