Abstract PO4-25-02: Long-range Deployment of Tumor-antigen Specific Cytotoxic T Lymphocytes Inhibits Lung Metastasis of Breast Cancer

Abstract Effector Immune Cell Deployment (EICD) refers to systemic deployment of anti-tumor effector immune cells in cancer patients, including the priming, circulation, trafficking, activity and fate of the immunocytes, and is a panorama to reflect the generation, distribution and development of anti-tumor immunity. Tumor antigen-specific T cells are the main component of effector immune cells in anti-tumor immune responses, but their systemic deployment in breast cancer patients and the underlying mechanisms remain largely unknown. Here, we identified a cluster of CD8+ T cell exhibiting tissue-resident memory (TRM) phenotype in the tumor-draining lymph nodes (TDLNs) of 487 breast cancer patients, whose abundancy specifically predicts improved lung, but not other target organ metastasis-free survival. Also, high lung CD8+ TRM infiltration is associated with lower metastatic burden in breast cancer patients. Using single-cell RNA sequencing, we observed that in multiple mouse cancer models, CD8+TRM accumulate at early tumor stages when lung metastasis was not identified. Functionally, the CD8+TRM isolated from pre-metastatic lungs of the animals were tumor antigen specific and cytotoxic to the tumor cells. Nevertheless, the abundancy of CD8+TRM in the lungs were dramatically decreased in the lungs upon metastasis establishment. Moreover, in Cd8cre/+ Itgaeloxp/+-diphtheria toxin receptor conditional knockout mice, we unambiguously demonstrated that specific depletion of the CD8+ TRM subset facilitates lung metastasis in vivo, while adoptive transfer of CD8+ TRM successfully inhibited lung metastasis and prolonged survival of the mice. Mechanistically, using cell-tracing techniques in the photo-convertible Kaede-Tg mice, we found that tumor-specific CD8+ TRM were generated in the TDLNs of the mice and were recruited to the lungs via CCL25/CCR9 signaling axis. However, the circulating exosomes secreted by primary tumor cells were taken up by alveolar macrophages and polarized them to release IDO1 and impaired anti-tumor T cell immunity, facilitating lung metastasis. More importantly, inhibition of IDO1 effectively retrieves TRM-mediated protection against lung metastasis. Collectively, we have revealed a cross-talk between tumor cells and the inflammatory environment of distant organs, which could drive lung metastasis by impairing EICD. Our findings also highlight the therapeutic potential of orchestrating EICD in turning “cold” metastatic tumor foci to “hot” ones. Citation Format: Yue Xing, Shicheng Su, Erwei Song. Long-range Deployment of Tumor-antigen Specific Cytotoxic T Lymphocytes Inhibits Lung Metastasis of Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-25-02.