CXCR6 expressing T cells: Functions and role in the control of tumors

Abstract

CXCR6 is a receptor for the chemokine CXCL16, which exists as a membrane or soluble form. CXCR6 is a marker for resident memory T (T_RM) cells that plays a role in immunosurveillance through their interaction with epithelial cells. The interaction of CXCR6 with CXCL16 expressed at the membrane of certain subpopulations of intratumor dendritic cells (DC) called DC3, ideally positions these CXCR6⁺ T cells to receive a proliferation signal from IL-15 also presented by DC3. Mice deficient in cxcr6 or blocking the interaction of CXCR6 with its ligand, experience a poorer control of tumor proliferation by CD8⁺ T cells, but also by NKT cells especially in the liver. Intranasal vaccination induces CXCL16 production in the lungs and is associated with infiltration by T_RM expressing CXCR6, which are then required for the efficacy of anti-tumor vaccination. Therapeutically, the addition of CXCR6 to specific CAR-T cells enhances their intratumoral accumulation and prolongs survival in animal models of pancreatic, ovarian and lung cancer. Finally, CXCR6 is part of immunological signatures that predict response to immunotherapy based on anti-PD-(L)1 in various cancers. 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 T_RM expressing CXCR6 and its potential use as a biomarker of response to immunotherapy opens new perspectives in cancer treatment.

Keywords: CAR T cell; CXCL16; CXCR6; dendritic cell; immunotherapy; mucosal vaccination; resident memory T cell.

Figure 1

Origin and differentiation of CXCR6⁺ T cells. CXCR6⁺ T cells are scarcely present in the lymph node and CXCR6 weakly expressed by both the progenitor (TCF1⁺) or the transitory (TCF1^-, CX3CR1⁺) T cell population. In the tumor microenvironment, the transitory T cells express CXCR6 which allows them to interact with the dendritic cell subpopulation (CCR7⁺ DC3) which expresses the membrane form of CXCL16. This contact promotes the interaction of IL-15 also expressed on the membrane of DC3 with the βγ chain of IL-15R expressed on CXCR6⁺ T cells. IL-15 induces the proliferation of CXCR6⁺ T cells and promotes their survival in the tumor microenvironment.

Figure 2

Strategy to regulate and induce CXCR6⁺ T cells.In light of the role of CXCR6⁺ T cells in tumor control, different strategies have been proposed to induce or increase their recruitment in the tumor microenvironment. As the majority of CXCR6⁺ T cells are included in the resident memory T cell population (T_RM), many strategies are common with those aimed at inducing T_RM.