Chemokine (C-X-C motif) ligand 9 (CXCL9) is a small cytokine belonging to the CXC chemokine family that is also known as monokine induced by gamma interferon (MIG). The CXCL9 is one of the chemokine which plays role to induce chemotaxis, promote differentiation and multiplication of leukocytes, and cause tissue extravasation.[5]
Chemokine (C-X-C motif) ligand 9 (CXCL9) exhibits the classic structure of CXC chemokines, characterized by a short and flexible N-terminal region, a well-ordered core stabilized by two disulfide bonds, three antiparallel beta-strands, and a C-terminal alpha-helix.[9] This conserved tertiary structure provides both stability and the necessary conformational flexibility at the N- and C-termini, enabling effective interactions with its receptor, CXCR3, and facilitating signal transduction essential for immune cell migration and activation.[9] The structural core is highly conserved among CXC chemokines, while variations in the loop regions contribute to differences in receptor binding and functional specificity.[9]
In immune cell differentiation, several reports indicate that CXCL9 promotes T helper 1 (Th1) polarization through CXCR3.[13] An in vivo model by Zohar et al. demonstrated that CXCL9 increased the transcription of T-bet and RORγ, leading to the polarization of Foxp3− type 1 regulatory (Tr1) cells or Th17 cells from naïve T cells via STAT1, STAT4, and STAT5phosphorylation.[13]
Several studies have shown that tumor-associated macrophages (TAMs) exert modulatory effects in the tumor microenvironment (TME), with the CXCL9/CXCR3 axis influencing TAM polarization. TAMs can exhibit opposing effects: M1 macrophages promote anti-tumor activity, while M2 macrophages support tumor progression. Oghumu et al. found that mice deficient in CXCR3 displayed increased IL-4 production and M2 polarization in a murine breast cancer model, accompanied by reduced innate and immune cell-mediated anti-tumor responses.[14]
Regarding immune cell activation, CXCL9 stimulates Th1 polarization and activation, leading to the production of IFN-γ, TNF-α, and IL-2. This enhances anti-tumor immunity by activating cytotoxic T lymphocytes (CTLs), NK cells, and macrophages.[15] Additionally, the IFN-γ-dependent immune activation loop further promotes CXCL9 release.[5]
Immune cells such as Th1 cells, CTLs, NK cells, and NKT cells exert anti-tumor effects against cancer cells via paracrine CXCL9/CXCR3 signaling in tumor models.[12] In contrast, autocrine CXCL9/CXCR3 signaling in cancer cells has been implicated in promoting cancer cell proliferation, angiogenesis, and metastasis.[citation needed]
Immune checkpoint regulation
The relationship between the CXCL9/CXCR3 axis and the PD-L1/PD-1 pathway is important in immune regulation. Programmed cell death protein 1 (PD-1) expression is increased on T cells within the tumor site compared to T cells in peripheral blood. Anti-PD-1 therapy can inhibit "immune escape" and enhance immune activation.[16] Peng et al. demonstrated that anti-PD-1 therapy not only enhanced T cell-mediated tumor regression but also increased the expression of IFN-γ, though not CXCL9, in bone marrow-derived cells.[16]
Blockade of the PD-L1/PD-1 axis in T cells may induce a positive feedback loop at the tumor site through the CXCL9/CXCR3 axis. Additionally, treatment with an anti-CTLA4 antibody led to a significant upregulation of this axis in pretreatment melanoma lesions from patients who exhibited a favorable clinical response to ipilimumab.[17]
^O'Donovan N, Galvin M, Morgan JG (1999). "Physical mapping of the CXC chemokine locus on human chromosome 4". Cytogenetics and Cell Genetics. 84 (1–2): 39–42. doi:10.1159/000015209. PMID10343098. S2CID8087808.
Erdel M, Laich A, Utermann G, Werner ER, Werner-Felmayer G (1998). "The human gene encoding SCYB9B, a putative novel CXC chemokine, maps to human chromosome 4q21 like the closely related genes for MIG (SCYB9) and INP10 (SCYB10)". Cytogenetics and Cell Genetics. 81 (3–4): 271–272. doi:10.1159/000015043. PMID9730616. S2CID46846304.
Stoof TJ, Flier J, Sampat S, Nieboer C, Tensen CP, Boorsma DM (June 2001). "The antipsoriatic drug dimethylfumarate strongly suppresses chemokine production in human keratinocytes and peripheral blood mononuclear cells". The British Journal of Dermatology. 144 (6): 1114–1120. doi:10.1046/j.1365-2133.2001.04220.x. PMID11422029. S2CID26364400.
Campbell JD, Stinson MJ, Simons FE, Rector ES, HayGlass KT (July 2001). "In vivo stability of human chemokine and chemokine receptor expression". Human Immunology. 62 (7): 668–678. doi:10.1016/S0198-8859(01)00260-9. PMID11423172.
