CXCL9, CXCL10, CXCL11/CXCR3 Axis for Immune Activation - A Target for Novel Cancer Therapy

Overview

Journal Cancer Treat Rev

Publisher Elsevier

Specialty Oncology

Date 2017 Dec 6

PMID 29207310

Citations 684

Authors

Ryuma Tokunaga

Wu Zhang

Madiha Naseem

Alberto Puccini

Martin D Berger

Shivani Soni

Michelle McSkane

Hideo Baba

Heinz-Josef Lenz

Affiliations

Soon will be listed here.

Abstract

Chemokines are proteins which induce chemotaxis, promote differentiation of immune cells, and cause tissue extravasation. Given these properties, their role in anti-tumor immune response in the cancer environment is of great interest. Although immunotherapy has shown clinical benefit for some cancer patients, other patients do not respond. One of the mechanisms of resistance to checkpoint inhibitors may be chemokine signaling. The CXCL9, -10, -11/CXCR3 axis regulates immune cell migration, differentiation, and activation, leading to tumor suppression (paracrine axis). However, there are some reports that show involvements of this axis in tumor growth and metastasis (autocrine axis). Thus, a better understanding of CXCL9, -10, -11/CXCR3 axis is necessary to develop effective cancer control. In this article, we summarize recent evidence regarding CXCL9, CXCL10, CXCL11/CXCR3 axis in the immune system and discuss their potential role in cancer treatment.

Citing Articles

Delayed viral clearance and altered inflammatory responses affect severity of SARS-CoV-2 infection in aged mice.

Lacasse E, Dubuc I, Gudimard L, Andrade A, Gravel A, Greffard K Immun Ageing. 2025; 22(1):11.

PMID: 40075368 PMC: 11899864. DOI: 10.1186/s12979-025-00503-1.

Longitudinal study on immunologic, lipoproteomic, and inflammatory responses indicates the safety of sequential COVID-19 vaccination.

Lang J, Bernal A, Wist J, Egan S, Bong S, Millet O J Mol Med (Berl). 2025; .

PMID: 40074874 DOI: 10.1007/s00109-025-02527-y.

Uncovering the rewired IAP-JAK regulatory axis as an immune-dependent vulnerability of LKB1-mutant lung cancer.

Shu C, Li J, Rui J, Fan D, Niu Q, Bai R Nat Commun. 2025; 16(1):2324.

PMID: 40057483 PMC: 11890758. DOI: 10.1038/s41467-025-57297-5.

Modulating tumor immunity using advanced microbiome therapeutics producing an indole metabolite.

Vaaben T, Lutzhoft D, Koulouktsis A, Dawoodi I, Stavnsbjerg C, Kvich L EMBO Rep. 2025; .

PMID: 40055466 DOI: 10.1038/s44319-025-00386-9.

Cxcl9-deficiency attenuates the progression of post-traumatic osteoarthritis in mice.

Donat A, Xie W, Jiang S, Brylka L, Schinke T, Rolvien T Inflamm Res. 2025; 74(1):48.

PMID: 40047894 PMC: 11885341. DOI: 10.1007/s00011-025-02013-8.

References

Gustafsson K, Junevik K, Werlenius O, Holmgren S, Karlsson-Parra A, Andersson P . Tumour-loaded α-type 1-polarized dendritic cells from patients with chronic lymphocytic leukaemia produce a superior NK-, NKT- and CD8+ T cell-attracting chemokine profile. Scand J Immunol. 2011; 74(3):318-326. DOI: 10.1111/j.1365-3083.2011.02580.x. View

Nakajima C, Mukai T, Yamaguchi N, Morimoto Y, Park W, Iwasaki M . Induction of the chemokine receptor CXCR3 on TCR-stimulated T cells: dependence on the release from persistent TCR-triggering and requirement for IFN-gamma stimulation. Eur J Immunol. 2002; 32(6):1792-801. DOI: 10.1002/1521-4141(200206)32:6<1792::AID-IMMU1792>3.0.CO;2-0. View

Monteagudo C, Martin J, Jorda E, Llombart-Bosch A . CXCR3 chemokine receptor immunoreactivity in primary cutaneous malignant melanoma: correlation with clinicopathological prognostic factors. J Clin Pathol. 2006; 60(6):596-9. PMC: 1955073. DOI: 10.1136/jcp.2005.032144. View

Curran M, Montalvo W, Yagita H, Allison J . PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010; 107(9):4275-80. PMC: 2840093. DOI: 10.1073/pnas.0915174107. View

Kim C, ROTT L, Kunkel E, Genovese M, Andrew D, Wu L . Rules of chemokine receptor association with T cell polarization in vivo. J Clin Invest. 2001; 108(9):1331-9. PMC: 209443. DOI: 10.1172/JCI13543. View

Fernandez-Poma S, Salas-Benito D, Lozano T, Casares N, Riezu-Boj J, Mancheno U . Expansion of Tumor-Infiltrating CD8 T cells Expressing PD-1 Improves the Efficacy of Adoptive T-cell Therapy. Cancer Res. 2017; 77(13):3672-3684. DOI: 10.1158/0008-5472.CAN-17-0236. View

Arenberg D, White E, Burdick M, Strom S, Strieter R . Improved survival in tumor-bearing SCID mice treated with interferon-gamma-inducible protein 10 (IP-10/CXCL10). Cancer Immunol Immunother. 2002; 50(10):533-8. PMC: 11032922. DOI: 10.1007/s00262-001-0231-9. View

Hong M, Puaux A, Huang C, Loumagne L, Tow C, Mackay C . Chemotherapy induces intratumoral expression of chemokines in cutaneous melanoma, favoring T-cell infiltration and tumor control. Cancer Res. 2011; 71(22):6997-7009. DOI: 10.1158/0008-5472.CAN-11-1466. View

Weng Y, Siciliano S, Waldburger K, Staruch M, Daugherty B, Gould S . Binding and functional properties of recombinant and endogenous CXCR3 chemokine receptors. J Biol Chem. 1998; 273(29):18288-91. DOI: 10.1074/jbc.273.29.18288. View

10.

Bronger H, Singer J, Windmuller C, Reuning U, Zech D, Delbridge C . CXCL9 and CXCL10 predict survival and are regulated by cyclooxygenase inhibition in advanced serous ovarian cancer. Br J Cancer. 2016; 115(5):553-63. PMC: 4997538. DOI: 10.1038/bjc.2016.172. View

11.

Hensbergen P, Wijnands P, Schreurs M, Scheper R, Willemze R, Tensen C . The CXCR3 targeting chemokine CXCL11 has potent antitumor activity in vivo involving attraction of CD8+ T lymphocytes but not inhibition of angiogenesis. J Immunother. 2005; 28(4):343-51. DOI: 10.1097/01.cji.0000165355.26795.27. View

12.

Xanthou G, Duchesnes C, Williams T, Pease J . CCR3 functional responses are regulated by both CXCR3 and its ligands CXCL9, CXCL10 and CXCL11. Eur J Immunol. 2003; 33(8):2241-50. DOI: 10.1002/eji.200323787. View

13.

Lu B, Humbles A, Bota D, Gerard C, Moser B, Soler D . Structure and function of the murine chemokine receptor CXCR3. Eur J Immunol. 1999; 29(11):3804-12. DOI: 10.1002/(SICI)1521-4141(199911)29:11<3804::AID-IMMU3804>3.0.CO;2-9. View

14.

Wendel M, Galani I, Suri-Payer E, Cerwenka A . Natural killer cell accumulation in tumors is dependent on IFN-gamma and CXCR3 ligands. Cancer Res. 2008; 68(20):8437-45. DOI: 10.1158/0008-5472.CAN-08-1440. View

15.

Bronger H, Kraeft S, Schwarz-Boeger U, Cerny C, Stockel A, Avril S . Modulation of CXCR3 ligand secretion by prostaglandin E2 and cyclooxygenase inhibitors in human breast cancer. Breast Cancer Res. 2012; 14(1):R30. PMC: 3496148. DOI: 10.1186/bcr3115. View

16.

Barash U, Zohar Y, Wildbaum G, Beider K, Nagler A, Karin N . Heparanase enhances myeloma progression via CXCL10 downregulation. Leukemia. 2014; 28(11):2178-87. PMC: 4185261. DOI: 10.1038/leu.2014.121. View

17.

Cambien B, Karimdjee B, Richard-Fiardo P, Bziouech H, Barthel R, Millet M . Organ-specific inhibition of metastatic colon carcinoma by CXCR3 antagonism. Br J Cancer. 2009; 100(11):1755-64. PMC: 2695685. DOI: 10.1038/sj.bjc.6605078. View

18.

Specht K, Harbeck N, Smida J, Annecke K, Reich U, Naehrig J . Expression profiling identifies genes that predict recurrence of breast cancer after adjuvant CMF-based chemotherapy. Breast Cancer Res Treat. 2008; 118(1):45-56. DOI: 10.1007/s10549-008-0207-y. View

19.

Tumeh P, Harview C, Yearley J, Shintaku I, Taylor E, Robert L . PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014; 515(7528):568-71. PMC: 4246418. DOI: 10.1038/nature13954. View

20.

Liu M, Matsumura N, Mandai M, Li K, Yagi H, Baba T . Classification using hierarchical clustering of tumor-infiltrating immune cells identifies poor prognostic ovarian cancers with high levels of COX expression. Mod Pathol. 2008; 22(3):373-84. DOI: 10.1038/modpathol.2008.187. View