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

M Di Pilato, R Kfuri-Rubens, JN Pruessmann, AJ Ozga… - Cell, 2021 - cell.com
M Di Pilato, R Kfuri-Rubens, JN Pruessmann, AJ Ozga, M Messemaker, BL Cadilha
Cell, 2021cell.com
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 …
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.
cell.com