CXCR6

CXCR receptors (C-X-C Motif Chemokine Receptors) are a family of chemokine receptors that belong to the group of G-protein-coupled receptors (GPCRs). There are currently 8 known chemokine receptors. These are transmembrane, G-protein-coupled receptors that are activated by the binding of one or more chemokines.

CXCR receptors play an essential role in the immune system by influencing the migration of immune cells to sites of inflammation or to tissues. Chemokines are signaling molecules produced by various cells. They form a family of chemoattractive molecules, of which more than 50 have been identified to date. Chemokines are divided into four main groups according to the number and spacing of conserved cysteines: CXC, CC, CX3C and C. They bind to their specific receptors (e.g. CXCR) and thus initiate a signaling cascade that controls the behavior of immune cells, including their movement, activation and differentiation. In individual cases, this can also influence tumor growth.

CXCR6 is a receptor for the chemokine CXCL16, which is present as a membrane-bound or soluble form (Mabrouk N et al. 2022). CXCR6 is a marker for resident memory T cells (TRM), which play a role in immune surveillance through their interaction with other cells. Thus, the receptor is involved in the recruitment of T cells and NK cells in inflammatory and tumor environments. CXCR6 is encoded by the gene of the same name (CXCR6 gene) which is localized on chromosome 3p21.31. The CXCR6 protein is a G-protein-coupled receptor with seven transmembrane domains. The cytotoxic T lymphocyte (CTL) response against tumors maintains the presence of stem cell-like memory cells that self-renew but also give rise to effector cell-like cells. The latter can gradually lose their antitumor activity, thereby assuming an epigenetically fixed, hypofunctional state, leading to tumor tolerance. The transformation of stem cell-like into effector cell-like CTLs involves extensive chemotactic reprogramming.

The expression of CXCR6 and the presentation of IL-15 are critical for the survival and local expansion of effector-like cytotoxic T lymphocytes in the tumor microenvironment. This demonstrates the importance of the CXCR6 receptor in tumor biology (Di Pilato M et al. 2021).

Finally, CXCR6 is part of immunological signatures that predict response to anti-PD-(L)1 based immunotherapy in different cancer types. In contrast, a protumoral role of CXCR6+T cells has also been reported, mainly in non-alcoholic steatohepatitis (NASH) due to a non-antigen-specific mechanism.

The targeting and amplification of antigen-specific TRM expressing CXCR6 and its potential use as a biomarker for response to immunotherapy opens new perspectives in cancer treatment (Mabrouk N et al. 2022).

1. Di Pilato M et al. (2021) CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment. Cell184:4512-4530.
2. Mabrouk N et al. (2022) CXCR6 expressing T cells: Functions and role in the control of tumors. Front Immunol 13:1022136.