Resident Memory T Cells in Tumor-Distant Tissues Fortify Against Metastasis Formation

Abstract

As a critical machinery for rapid pathogen removal, resident memory T cells (TRMs) are locally generated after initial virus encounter. However, their development accompanying tumorigenesis remains elusive. In a murine breast cancer model, we identified that TRMs developed in the tumor and in the contralateral distant mammary mucosa tissue. Single-cell RNA-sequencing of intratumor and distant mucosal TRMs revealed two phenotypically distinct populations representing their active versus quiescent phases. These T RM s in different tissue compartments share the same TCR clonotypes and transcriptomes with a subset of intratumoral effector/effector memory T cells (TEff/EMs), indicating their developmental ontogeny. Furthermore, we identified that CXCL16 is produced by tumor cells and CXCR6 - TEff/EMs are the major subset that preferentially egresses the tumor to form distant TRMs. Functionally, releasing CXCR6 retention in the primary tumor leads to superior control against lung metastases. This immunologic fortification implies a new strategy to prevent metastasis in clinical oncology.