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

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