Mammalian protein found in Homo sapiens
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.
[3]
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 .
[4]
Tumor -infiltrating
lymphocytes are a key for clinical outcomes and prediction of the response to
checkpoint inhibitors .
[5] In vivo studies suggest the axis plays a tumorigenic role by increasing tumor proliferation and
metastasis .[
citation needed ] CXCL9 predominantly mediates
lymphocytic infiltration to the focal sites and suppresses tumor growth.
[6]
It is closely related to two other CXC chemokines called
CXCL10 and
CXCL11 , whose genes are located near the
gene for CXCL9 on human
chromosome 4 .
[7]
[8] CXCL9,
CXCL10 and
CXCL11 all elicit their chemotactic functions by interacting with the
chemokine receptor
CXCR3 .
[9]
Biomarkers
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 .
[10]
[11]
This
chemokine has also been associated as a
biomarker for diagnosing
Q fever infections.
[12]
Interactions
CXCL9 has been shown to
interact with
CXCR3 .
[13]
[14]
CXCL9 in immune reactions
For immune cell differentiation, some reports show that CXCL9 lead to Th1 polarization through CXCR3.
[15] In vivo model by Zohar et al. showed that CXCL9, drove increased transcription of
T-bet and
RORγ , leading to the polarization of
Foxp3 − type 1 regulatory (Tr1) cells or
T helper 17 (Th17) from naive T cells via
STAT1 ,
STAT4 , and
STAT5
phosphorylation .
[15]
Several studies have shown that
tumor-associated macrophages (TAMs) play modulatory activities in the TME, and the CXCL9/CXCR3 axis impacts TAMs polarization. The TAMs have opposite effects;
M1 for anti-tumor activities, and
M2 for pro-tumor activities. Oghumu et al. clarified that CXCR3 deficient mice displayed increased
IL-4 production and M2 polarization in a murine breast cancer model, and decreased innate and immune cell-mediated anti-tumor responses.
[16]
For immune cell activation, CXCL9 stimulate immune cells through Th1 polarization and activation. Th1 cells produce
IFN-γ ,
TNF-α ,
IL-2 and enhance anti-tumor immunity by stimulating CTLs,
NK cells and
macrophages .
[17] The
IFN-γ -dependent immune activation loop also promotes CXCL9 release.
[3]
Immune cells, like Th1, CTLs,
NK cells, and
NKT cells, show anti-tumor effect against
cancer cells through paracrine CXCL9/CXCR3 in
tumor models.
[6] The
autocrine CXCL9/CXCR3 signaling in
cancer cells increases cancer cell proliferation, angiogenesis, and metastasis.[
citation needed ]
CXCL9/CXCR3 and the PDL-1/PD-1
The relationship between CXCL9/CXCR3 and the
PDL-1 /
PD-1 is an important area of research. Programmed cell death-1 (
PD-1 ) shows increased expression on T cells at the
tumor site compared to T cells present in the peripheral blood, and anti-
PD-1 therapy can inhibit “immune escape” and the immune activation.
[18] Peng et al. showed that anti-
PD-1 could not only enhance T cell-mediated tumor regression but also increase the expression of
IFN-γ but not CXCL9 by
bone marrow –derived cells.
[18] Blockade of the
PDL-1 /
PD-1 axis in T cells may trigger a positive feedback loop at the tumor site through the CXCL9/CXCR3 axis. Also using anti-
CTLA4 antibody, this axis was significantly up-regulated in pretreatment
melanoma lesions in patients with good clinical response after
ipilimumab administration.
[19]
CXCL9 and melanoma
CXCL9 has also been identified as candidate
biomarker of adoptive
T cell transfer
therapy in
metastatic
melanoma .
[20] 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.
[3]
References
^
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b
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^
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^ Tensen CP, Flier J, Van Der Raaij-Helmer EM, Sampat-Sardjoepersad S, Van Der Schors RC, Leurs R, Scheper RJ, Boorsma DM, Willemze R (May 1999).
"Human IP-9: A keratinocyte-derived high affinity CXC-chemokine ligand for the IP-10/Mig receptor (CXCR3)" . The Journal of Investigative Dermatology . 112 (5): 716–22.
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^ Altara R, Gu YM, Struijker-Boudier HA, Thijs L, Staessen JA, Blankesteijn WM (2015).
"Left Ventricular Dysfunction and CXCR3 Ligands in Hypertension: From Animal Experiments to a Population-Based Pilot Study" . PLOS ONE . 10 (10): e0141394.
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2015PLoSO..1041394A .
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^ Altara R, Manca M, Hessel MH, Gu Y, van Vark LC, Akkerhuis KM, Staessen JA, Struijker-Boudier HA, Booz GW, Blankesteijn WM (August 2016).
"CXCL10 Is a Circulating Inflammatory Marker in Patients with Advanced Heart Failure: a Pilot Study" . Journal of Cardiovascular Translational Research . 9 (4): 302–14.
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10.1007/s12265-016-9703-3 .
PMID
27271043 .
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41188765 .
^ Jansen AF, Schoffelen T, Textoris J, Mege JL, Nabuurs-Franssen M, Raijmakers RP, Netea MG, Joosten LA, Bleeker-Rovers CP, van Deuren M (August 2017).
"CXCL9, a promising biomarker in the diagnosis of chronic Q fever" . BMC Infectious Diseases . 17 (1): 556.
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5551022 .
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^ 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 (June 2003).
"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" . The Journal of Experimental Medicine . 197 (11): 1537–49.
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2193908 .
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9660793 .
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4001543 .
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24713654 .
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4137960 .
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^
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Further reading
Farber JM (July 1990).
"A macrophage mRNA selectively induced by gamma-interferon encodes a member of the platelet factor 4 family of cytokines" . Proceedings of the National Academy of Sciences of the United States of America . 87 (14): 5238–42.
Bibcode :
1990PNAS...87.5238F .
doi :
10.1073/pnas.87.14.5238 .
PMC
54298 .
PMID
2115167 .
Liao F, Rabin RL, Yannelli JR, Koniaris LG, Vanguri P, Farber JM (November 1995).
"Human Mig chemokine: biochemical and functional characterization" . The Journal of Experimental Medicine . 182 (5): 1301–14.
doi :
10.1084/jem.182.5.1301 .
PMC
2192190 .
PMID
7595201 .
Farber JM (April 1993).
"HuMig: a new human member of the chemokine family of cytokines" . Biochemical and Biophysical Research Communications . 192 (1): 223–30.
doi :
10.1006/bbrc.1993.1403 .
PMID
8476424 .
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): 271–2.
doi :
10.1159/000015043 .
PMID
9730616 .
S2CID
46846304 .
Jenh CH, Cox MA, Kaminski H, Zhang M, Byrnes H, Fine J, Lundell D, Chou CC, Narula SK, Zavodny PJ (April 1999).
"Cutting edge: species specificity of the CC chemokine 6Ckine signaling through the CXC chemokine receptor CXCR3: human 6Ckine is not a ligand for the human or mouse CXCR3 receptors" . Journal of Immunology . 162 (7): 3765–9.
doi :
10.4049/jimmunol.162.7.3765 .
PMID
10201891 .
S2CID
23946439 .
Rabin RL, Park MK, Liao F, Swofford R, Stephany D, Farber JM (April 1999).
"Chemokine receptor responses on T cells are achieved through regulation of both receptor expression and signaling" . Journal of Immunology . 162 (7): 3840–50.
doi :
10.4049/jimmunol.162.7.3840 .
PMID
10201901 .
S2CID
39401025 .
Shields PL, Morland CM, Salmon M, Qin S, Hubscher SG, Adams DH (December 1999).
"Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver" . Journal of Immunology . 163 (11): 6236–43.
doi :
10.4049/jimmunol.163.11.6236 .
PMID
10570316 .
S2CID
37624763 .
Jinquan T, Jing C, Jacobi HH, Reimert CM, Millner A, Quan S, Hansen JB, Dissing S, Malling HJ, Skov PS, Poulsen LK (August 2000).
"CXCR3 expression and activation of eosinophils: role of IFN-gamma-inducible protein-10 and monokine induced by IFN-gamma" . Journal of Immunology . 165 (3): 1548–56.
doi :
10.4049/jimmunol.165.3.1548 .
PMID
10903763 .
Loetscher P, Pellegrino A, Gong JH, Mattioli I, Loetscher M, Bardi G, Baggiolini M, Clark-Lewis I (February 2001).
"The ligands of CXC chemokine receptor 3, I-TAC, Mig, and IP10, are natural antagonists for CCR3" . The Journal of Biological Chemistry . 276 (5): 2986–91.
doi :
10.1074/jbc.M005652200 .
PMID
11110785 .
Romagnani P, Annunziato F, Lazzeri E, Cosmi L, Beltrame C, Lasagni L, Galli G, Francalanci M, Manetti R, Marra F, Vanini V, Maggi E, Romagnani S (February 2001).
"Interferon-inducible protein 10, monokine induced by interferon gamma, and interferon-inducible T-cell alpha chemoattractant are produced by thymic epithelial cells and attract T-cell receptor (TCR) alphabeta+ CD8+ single-positive T cells, TCRgammadelta+ T cells, and natural killer-type cells in human thymus" . Blood . 97 (3): 601–7.
doi :
10.1182/blood.V97.3.601 .
PMID
11157474 .
Dwinell MB, Lügering N, Eckmann L, Kagnoff MF (January 2001).
"Regulated production of interferon-inducible T-cell chemoattractants by human intestinal epithelial cells" . Gastroenterology . 120 (1): 49–59.
doi :
10.1053/gast.2001.20914 .
PMID
11208713 .
Lambeir AM, Proost P, Durinx C, Bal G, Senten K, Augustyns K, Scharpé S, Van Damme J, De Meester I (August 2001).
"Kinetic investigation of chemokine truncation by CD26/dipeptidyl peptidase IV reveals a striking selectivity within the chemokine family" . The Journal of Biological Chemistry . 276 (32): 29839–45.
doi :
10.1074/jbc.M103106200 .
PMID
11390394 .
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): 1114–20.
doi :
10.1046/j.1365-2133.2001.04220.x .
PMID
11422029 .
S2CID
26364400 .
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): 668–78.
doi :
10.1016/S0198-8859(01)00260-9 .
PMID
11423172 .
Scapini P, Laudanna C, Pinardi C, Allavena P, Mantovani A, Sozzani S, Cassatella MA (July 2001).
"Neutrophils produce biologically active macrophage inflammatory protein-3alpha (MIP-3alpha)/CCL20 and MIP-3beta/CCL19" . European Journal of Immunology . 31 (7): 1981–8.
doi :
10.1002/1521-4141(200107)31:7<1981::AID-IMMU1981>3.0.CO;2-X .
PMID
11449350 .
Gillitzer R (August 2001). "Inflammation in human skin: a model to study chemokine-mediated leukocyte migration in vivo". The Journal of Pathology . 194 (4): 393–4.
doi :
10.1002/1096-9896(200108)194:4<393::AID-PATH907>3.0.CO;2-7 .
PMID
11523044 .
S2CID
32739376 .
Romagnani P, Rotondi M, Lazzeri E, Lasagni L, Francalanci M, Buonamano A, Milani S, Vitti P, Chiovato L, Tonacchera M, Bellastella A, Serio M (July 2002).
"Expression of IP-10/CXCL10 and MIG/CXCL9 in the thyroid and increased levels of IP-10/CXCL10 in the serum of patients with recent-onset Graves' disease" . The American Journal of Pathology . 161 (1): 195–206.
doi :
10.1016/S0002-9440(10)64171-5 .
PMC
1850693 .
PMID
12107104 .
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