CXCL9

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.{{cite journal | vauthors = Valdés N, Espinoza D, Pareja-Barrueto C, Olate N, Barraza-Rojas F, Benavides-Larenas A, Cortés M, Imarai M | title = Expression and regulation of the CXCL9-11 chemokines and CXCR3 receptor in Atlantic salmon (Salmo salar) | journal = Frontiers in Immunology | volume = 15 | issue = | pages = 1455457 | date = 2024 | pmid = 39301034 | pmc = 11410577 | doi = 10.3389/fimmu.2024.1455457 | doi-access = free | url = }} 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. The structural core is highly conserved among CXC chemokines, while variations in the loop regions contribute to differences in receptor binding and functional specificity.

The CXCL9/CXCR3 receptor regulates immune cell migration, differentiation, and activation. Immune reactivity occurs through recruitment of immune cells, such as cytotoxic lymphocytes (CTLs), natural killer (NK) cells, NKT cells, and macrophages. Th1 polarization also activates the immune cells in response to IFN-γ.{{cite book | vauthors = Schoenborn JR, Wilson CB | title = Regulation of interferon-gamma during innate and adaptive immune responses | series = Advances in Immunology | volume = 96 | pages = 41–101 | date = 2007 | pmid = 17981204 | doi = 10.1016/s0065-2776(07)96002-2 | publisher = Elsevier | isbn = 978-0-12-373709-0 }} Tumor-infiltrating lymphocytes are a key for clinical outcomes and prediction of the response to checkpoint inhibitors.{{cite journal | vauthors = Fernandez-Poma SM, Salas-Benito D, Lozano T, Casares N, Riezu-Boj JI, Mancheño U, Elizalde E, Alignani D, Zubeldia N, Otano I, Conde E, Sarobe P, Lasarte JJ, Hervas-Stubbs S | title = + T cells Expressing PD-1 Improves the Efficacy of Adoptive T-cell Therapy | journal = Cancer Research | volume = 77 | issue = 13 | pages = 3672–3684 | date = July 2017 | pmid = 28522749 | doi = 10.1158/0008-5472.CAN-17-0236 | doi-access = free }} In vivo studies suggest the axis plays a tumorigenic role by increasing tumor proliferation and metastasis.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}} CXCL9 predominantly mediates lymphocytic infiltration to the focal sites and suppresses tumor growth.{{Cite journal | vauthors = Gorbachev AV, Kobayashi H, Kudo D, Tannenbaum CS, Finke JH, Shu S, Farber JM, Fairchild RL | title = CXC Chemokine Ligand 9/Monokine Induced by IFN- Production by Tumor Cells Is Critical for T Cell-Mediated Suppression of Cutaneous Tumors | journal = Journal of Immunology | location = Baltimore, Md. | volume = 178 | issue = 4 | pages = 2278–2286 | date = 2007-02-15 | pmid = 17277133 | doi = 10.4049/jimmunol.178.4.2278 | issn = 0022-1767 | doi-access = free }}

In immune cell differentiation, several reports indicate that CXCL9 promotes T helper 1 (Th1) polarization through CXCR3.{{cite journal | vauthors = Zohar Y, Wildbaum G, Novak R, Salzman AL, Thelen M, Alon R, Barsheshet Y, Karp CL, Karin N | title = CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis | journal = The Journal of Clinical Investigation | volume = 124 | issue = 5 | pages = 2009–2022 | date = May 2014 | pmid = 24713654 | pmc = 4001543 | doi = 10.1172/JCI71951 }}{{Expression of Concern|doi=10.1172/JCI97015|pmid=28846074}} 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 STAT5 phosphorylation.

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.{{cite journal | vauthors = Oghumu S, Varikuti S, Terrazas C, Kotov D, Nasser MW, Powell CA, Ganju RK, Satoskar AR | title = CXCR3 deficiency enhances tumor progression by promoting macrophage M2 polarization in a murine breast cancer model | journal = Immunology | volume = 143 | issue = 1 | pages = 109–119 | date = September 2014 | pmid = 24679047 | pmc = 4137960 | doi = 10.1111/imm.12293 }}

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.{{cite journal | vauthors = Mosser DM, Edwards JP | title = Exploring the full spectrum of macrophage activation | journal = Nature Reviews. Immunology | volume = 8 | issue = 12 | pages = 958–969 | date = December 2008 | pmid = 19029990 | pmc = 2724991 | doi = 10.1038/nri2448 }} Additionally, the IFN-γ-dependent immune activation loop further promotes CXCL9 release.

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. In contrast, autocrine CXCL9/CXCR3 signaling in cancer cells has been implicated in promoting cancer cell proliferation, angiogenesis, and metastasis.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}}

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.{{cite journal | vauthors = Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y, Yagita H, Overwijk WW, Lizée G, Radvanyi L, Hwu P | title = PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines | journal = Cancer Research | volume = 72 | issue = 20 | pages = 5209–5218 | date = October 2012 | pmid = 22915761 | pmc = 3476734 | doi = 10.1158/0008-5472.CAN-12-1187 }} 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.

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.{{cite journal | vauthors = Ji RR, Chasalow SD, Wang L, Hamid O, Schmidt H, Cogswell J, Alaparthy S, Berman D, Jure-Kunkel M, Siemers NO, Jackson JR, Shahabi V | title = An immune-active tumor microenvironment favors clinical response to ipilimumab | journal = Cancer Immunology, Immunotherapy | volume = 61 | issue = 7 | pages = 1019–1031 | date = July 2012 | pmid = 22146893 | pmc = 11028506 | doi = 10.1007/s00262-011-1172-6 | s2cid = 8464711 }}

CXCL9, -10, -11 have proven to be valid biomarkers for the development of heart failure and left ventricular dysfunction, suggesting an underlining pathophysiological relation between levels of these chemokines and the development of adverse cardiac remodeling.{{cite journal | vauthors = Altara R, Gu YM, Struijker-Boudier HA, Thijs L, Staessen JA, Blankesteijn WM | title = Left Ventricular Dysfunction and CXCR3 Ligands in Hypertension: From Animal Experiments to a Population-Based Pilot Study | journal = PLOS ONE | volume = 10 | issue = 10 | pages = e0141394 | date = 2015 | pmid = 26506526 | pmc = 4624781 | doi = 10.1371/journal.pone.0141394 | bibcode = 2015PLoSO..1041394A | doi-access = free }}{{cite journal | vauthors = Altara R, Manca M, Hessel MH, Gu Y, van Vark LC, Akkerhuis KM, Staessen JA, Struijker-Boudier HA, Booz GW, Blankesteijn WM | title = CXCL10 Is a Circulating Inflammatory Marker in Patients with Advanced Heart Failure: a Pilot Study | journal = Journal of Cardiovascular Translational Research | volume = 9 | issue = 4 | pages = 302–314 | date = August 2016 | pmid = 27271043 | doi = 10.1007/s12265-016-9703-3 | s2cid = 41188765 | url = https://cris.maastrichtuniversity.nl/en/publications/f1f5f074-054e-46eb-beab-42900e7cf1e7 }}

This chemokine has also been associated as a biomarker for diagnosing Q fever infections.{{cite journal | vauthors = Jansen AF, Schoffelen T, Textoris J, Mege JL, Nabuurs-Franssen M, Raijmakers RP, Netea MG, Joosten LA, Bleeker-Rovers CP, van Deuren M | title = CXCL9, a promising biomarker in the diagnosis of chronic Q fever | journal = BMC Infectious Diseases | volume = 17 | issue = 1 | pages = 556 | date = August 2017 | pmid = 28793883 | pmc = 5551022 | doi = 10.1186/s12879-017-2656-6 | doi-access = free }}

CXCL9 has also been identified as candidate biomarker of adoptive T cell transfer therapy in metastatic melanoma.{{cite journal | vauthors = Bedognetti D, Spivey TL, Zhao Y, Uccellini L, Tomei S, Dudley ME, Ascierto ML, De Giorgi V, Liu Q, Delogu LG, Sommariva M, Sertoli MR, Simon R, Wang E, Rosenberg SA, Marincola FM | title = CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2 | journal = British Journal of Cancer | volume = 109 | issue = 9 | pages = 2412–2423 | date = October 2013 | pmid = 24129241 | pmc = 3817317 | doi = 10.1038/bjc.2013.557 }} The role of CXCL9/CXCR3 in TME and immune response - this plays a critical role in immune activation through paracrine signaling, impacting efficacy of cancer treatments.

CXCL9 has been shown to interact with CXCR3.{{cite journal | vauthors = Lasagni L, Francalanci M, Annunziato F, Lazzeri E, Giannini S, Cosmi L, Sagrinati C, Mazzinghi B, Orlando C, Maggi E, Marra F, Romagnani S, Serio M, Romagnani P | title = An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4 | journal = The Journal of Experimental Medicine | volume = 197 | issue = 11 | pages = 1537–1549 | date = June 2003 | pmid = 12782716 | pmc = 2193908 | doi = 10.1084/jem.20021897 }}{{cite journal | vauthors = Weng Y, Siciliano SJ, Waldburger KE, Sirotina-Meisher A, Staruch MJ, Daugherty BL, Gould SL, Springer MS, DeMartino JA | title = Binding and functional properties of recombinant and endogenous CXCR3 chemokine receptors | journal = The Journal of Biological Chemistry | volume = 273 | issue = 29 | pages = 18288–18291 | date = July 1998 | pmid = 9660793 | doi = 10.1074/jbc.273.29.18288 | doi-access = free }}

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{{refend}}

• {{UCSC gene info|CXCL9}}

{{Chemokines}}

{{Chemokine receptor modulators}}

Category:Cytokines