CXCR3 Ligands in Cancer and Autoimmunity, Chemoattraction of Effector T Cells, and Beyond

Abstract

CXCR3 is a chemokine receptor with three ligands; CXCL9, CXCL10, and CXCL11. CXCL11 binds CXCR3 with a higher affinity than the other ligands leading to receptor internalization. Long ago we reported that one of these chemokines, CXCL10, not only attracts CXCR3+ CD4+ and CD8+ effector T cells to sites of inflammation, but also direct their polarization into highly potent effector T cells. Later we showed that CXCL11 directs the linage development of T-regulatory-1 cells (Tr1). We also observed that CXCL11 and CXCL10 induce different signaling cascades via CXCR3. Collectively this suggests that CXCR3 ligands differentially regulate the biological function of T cells via biased signaling. It is generally accepted that tumor cells evolved to express several chemokine receptors and secrete their ligands. Vast majority of these chemokines support tumor growth by different mechanisms that are discussed. We suggest that CXCL10 and possibly CXCL9 differ from other chemokines by their ability to restrain tumor growth and enhance anti-tumor immunity. Along with this an accumulating number of studies showed in various human cancers a clear association between poor prognosis and low expression of CXCL10 at tumor sites, and vice versa. Finally, we discuss the possibility that CXCL9 and CXCL10 may differ in their biological function via biased signaling and its possible relevance to cancer immunotherapy. The current mini review focuses on exploring the role of CXCR3 ligands in directing the biological properties of CD4+ and CD8+ T cells in the context of cancer and autoimmunity. We believe that the combined role of these chemokines in attracting T cells and also directing their biological properties makes them key drivers of immune function.

Type 2 Innate Lymphoid Cells Induce CNS Demyelination in an HSV-IL-2 Mouse Model of Multiple Sclerosis

“…CCL5 plays a primary role in the inflammatory immune response and has been implicated in EAE and MS ( Gonzalez-Amaro and Sanchez-Madrid, 2002 ; Jee et al., 2002 ). Overall, the role of CCL5 and CXCL10 in inflammatory autoimmunity, particularly in neuroinflammation, is controversial ( Karin, 2020 ; Lalor and Segal, 2013 ; Mills Ko et al., 2014 ; Muller et al., 2010 ). Both CCL5 and CXCL10 are chemotactic for T cells and play an active role in recruiting leukocytes into inflammatory sites.…”

CXCL11 Correlates With Antitumor Immunity and an Improved Prognosis in Colon Cancer

“…The chemokine ligand C-X-C motif chemokine ligand 11 (CXCL11), also known as IFN-inducible T cell α chemoattractant (I-TAC), mediates recruitment of T cells, natural killer (NK) cells and monocytes/macrophages at sites of infection, predominantly through the cognate G-protein coupled receptor CXCR3, like CXCL9 and CXCL10 ( Colvin et al, 2004 ; Karin, 2020 ). This signaling axis has been implicated in several physiological activities, including immune cell migration, differentiation, and activation ( Tokunaga et al, 2018 ).…”

Loss of Rnf31 and Vps4b sensitizes pancreatic cancer to T cell-mediated killing

“…3e, f]. Notably, the Cxcr3-Stat3 signaling axis has previously been described to enhance PDA aggressiveness and contribute to an immune suppressive environment through inducing PD-L1 (CD274) expression 25,26 , and low expression of these chemokines is correlated with a better prognosis in human PDA patients [Supplementary Fig. 3e].…”