CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment

Cytotoxic T lymphocyte (CTL) responses against tumors are maintained by stem-like memory cells that self-renew but also give rise to effector-like cells. The latter gradually lose their anti-tumor activity and acquire an epigenetically fixed, hypofunctional state, leading to tumor tolerance. Here, w...

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Bibliographic Details
Published in:Cell 2021-08, Vol.184 (17), p.4512-4530.e22
Main Authors: Di Pilato, Mauro, Kfuri-Rubens, Raphael, Pruessmann, Jasper N., Ozga, Aleksandra J., Messemaker, Marius, Cadilha, Bruno L., Sivakumar, Ramya, Cianciaruso, Chiara, Warner, Ross D., Marangoni, Francesco, Carrizosa, Esteban, Lesch, Stefanie, Billingsley, James, Perez-Ramos, Daniel, Zavala, Fidel, Rheinbay, Esther, Luster, Andrew D., Gerner, Michael Y., Kobold, Sebastian, Pittet, Mikael J., Mempel, Thorsten R.
Format: Article
Language:English
Subjects:
Animals
B7-H1 Antigen - metabolism
CCR7+ dendritic cells
Cell Communication
Cell Movement
Cell Proliferation
Cell Survival
Chemokine CXCL16
CTL
CXCL16
CXCR6
Dendritic Cells - metabolism
IL-15
Interleukin-12 - metabolism
Interleukin-15 - metabolism
Ligands
Lymph Nodes - metabolism
Melanoma - immunology
Melanoma - pathology
Mice
Mice, Inbred C57BL
multiphoton intravital microscopy
Receptors, CXCR6 - metabolism
scRNA-seq
T-Lymphocytes, Cytotoxic - immunology
TCF-1
TCGA
Tumor Microenvironment
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Summary:Cytotoxic T lymphocyte (CTL) responses against tumors are maintained by stem-like memory cells that self-renew but also give rise to effector-like cells. The latter gradually lose their anti-tumor activity and acquire an epigenetically fixed, hypofunctional state, leading to tumor tolerance. Here, we show that the conversion of stem-like into effector-like CTLs involves a major chemotactic reprogramming that includes the upregulation of chemokine receptor CXCR6. This receptor positions effector-like CTLs in a discrete perivascular niche of the tumor stroma that is densely occupied by CCR7+ dendritic cells (DCs) expressing the CXCR6 ligand CXCL16. CCR7+ DCs also express and trans-present the survival cytokine interleukin-15 (IL-15). CXCR6 expression and IL-15 trans-presentation are critical for the survival and local expansion of effector-like CTLs in the tumor microenvironment to maximize their anti-tumor activity before progressing to irreversible dysfunction. These observations reveal a cellular and molecular checkpoint that determines the magnitude and outcome of anti-tumor immune responses. [Display omitted] •CXCR6 is critical for sustained tumor control mediatedby CD8+ cytotoxic T cells (CTLs)•CXCR6 optimizes CTL interactions with the CCR7+ DC3 state of conventional DCs•DC3s trans-present IL-15 to TCF-1neg effector-like CTLs to sustain their survival in the TME•DC3s densely cluster in T cell-rich perivascular niches of the tumor stroma Intravital imaging reveals how the chemokine receptor CXCR6 positions CD8+ cytotoxic T cells in a distinct perivascular niche of the tumor stroma that is populated by CCR7+ dendritic cells expressing the CXCR6-ligand CXCL16 and trans-presenting the cytokine IL-15. This molecular checkpoint allows for the survival and expansion of CD8+ T cells to enable a potent anti-tumor immune response.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2021.07.015