Abstract
SUMMARYAs 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 (TEff/EMs), indicating their developmental ontogeny. Furthermore, CXCL16 is highly produced by tumor cells and CXCR6− TEff/EMs 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.
Highlights
The formation of memory T cells is the hallmark of adaptive immunity, which provides rapid and robust protection against bacteria, virus, or tumor during antigen re-encounter
Using CD103 (Itgae), a specified integrin molecule that binds E-cadherin on the epithelial barrier (Cepek et al, 1994), TRMs reside in mucosal tissues and are an integral component of the adaptive immune machinery against viral re-challenge, including vaccinia virus, influenza, and herpes simplex virus (HSV) (Ariotti et al, 2014; Iijima and Iwasaki, 2015; Jiang et al, 2012; Teijaro et al, 2011; Wu et al, 2014)
While we initially included the distant mammary gland mucosa as a TRM-free control, we found that CD8+CD103+ TRMs developed in all tissues and their frequency increased with tumor growth, even in the distant mucosa (Figure 1A)
Summary
The formation of memory T cells is the hallmark of adaptive immunity, which provides rapid and robust protection against bacteria, virus, or tumor during antigen re-encounter. TCMs are long-lived, quiescent, and stem cell-like They bear the chemokine receptor CCR7 and the cell adhesion molecule CD62L, allowing them to enter and patrol secondary lymphoid organs (Unsoeld et al, 2002; von Andrian and Mackay, 2000). Upon antigen recognition, they differentiate with multipotent capacity (Williams and Bevan, 2007). Unlike TEMs, TRMs release chemokines to recruit T cells, including circulating TEMs, to the infected tissue for intensified immune protection (Schenkel and Masopust, 2014)
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