Resident memory T cells in tumor-distant tissues fortify against metastasis formation.

As a critical machinery for rapid pathogen removal, resident memory T cells (Ts) are locally generated after the initial encounter. However, their development accompanying tumorigenesis remains elusive. Using a murine breast cancer model, we show that Ts develop in the tumor, the contralateral mammary mucosa, and the pre-metastatic lung. Single-cell RNA sequencing of Ts reveals two phenotypically distinct populations representing their active versus quiescent phases. These Ts in different tissue compartments share the same TCR clonotypes and transcriptomes with a subset of intratumoral effector/effector memory T cells (Ts), indicating their developmental ontogeny. Furthermore, CXCL16 is highly produced by tumor cells and CXCR6 Ts are the major subset preferentially egressing the tumor to form distant Ts. Functionally, releasing CXCR6 retention in the primary tumor amplifies tumor-derived Ts in the lung and leads to superior protection against metastases. This immunologic fortification suggests a potential strategy to prevent metastasis in clinical oncology.