Tumor Microenvironment pp 45-51 | Cite as
The Multifaceted Roles of CXCL9 Within the Tumor Microenvironment
- 7 Citations
- 1 Mentions
- 1.8k Downloads
Abstract
Chemokines are soluble proteins that orchestrate cell migration in a regulated concentration gradient. During early stages of tumor development, chemokines shape the immune landscape of tumor microenvironment. CXCL9, also known as monokine induced by gamma-interferon (MIG), can be produced during inflammatory conditions by myeloid cells within the tumor microenvironment. It attracts cells expressing the CXCR3 receptor including activated T and NK cells and has been shown to play a role in responses to immune checkpoint therapy. Overexpression of CXCL9 has also shown to reduce tumor progression and metastasis via the inhibition of angiogenesis. Conversely, CXCL9 can act directly on tumor cells expressing the CXCR3 receptor to promote cell migration and epithelial mesenchymal transition. In this chapter we discuss the anti- and pro-tumoral features of CXCL9 within the tumor microenvironment.
Keywords
CXCL9 MIG CXCR3 Chemokines Tumor microenvironment Inflammation T cells NK cells Tumors Migration Epithelial mesenchymal transition Metastasis Angiogenesis CXC chemokines BiomarkerReferences
- 1.Vicari AP, Caux C (2002) Chemokines in cancer. Cytokine Growth Factor Rev 13(2):143–154PubMedCrossRefGoogle Scholar
- 2.Vignali D, Kallikourdis M (2017) Improving homing in T cell therapy. Cytokine Growth Factor Rev 36:107–116PubMedCrossRefGoogle Scholar
- 3.Groom JR, Luster AD (2011) CXCR3 ligands: redundant, collaborative and antagonistic functions. Immunol Cell Biol 89(2):207–215PubMedCrossRefGoogle Scholar
- 4.Kunz M, Toksoy A, Goebeler M, Engelhardt E, Brocker E, Gillitzer R (1999) Strong expression of the lymphoattractant C-X-C chemokine Mig is associated with heavy infiltration of T cells in human malignant melanoma. J Pathol 189(4):552–558PubMedCrossRefGoogle Scholar
- 5.Dangaj D, Bruand M, Grimm AJ, Ronet C, Barras D, Duttagupta PA et al (2019) Cooperation between constitutive and inducible chemokines enables T cell engraftment and immune attack in solid tumors. Cancer Cell 35(6):885PubMedCrossRefGoogle Scholar
- 6.Gorbachev A, Petro M (2011) Expression of CXCL9/Mig in the tumor microenvironment is critical for recruitment of CD8 T cells and suppression of cutaneous tumor growth. J Immunol 186:48.4Google Scholar
- 7.Kerbel RS (2008) Tumor angiogenesis. N Engl J Med 358(19):2039–2049PubMedPubMedCentralCrossRefGoogle Scholar
- 8.Keeley EC, Mehrad B, Strieter RM (2011) Chemokines as mediators of tumor angiogenesis and neovascularization. Exp Cell Res 317(5):685–690PubMedCrossRefGoogle Scholar
- 9.Lasagni L, Francalanci M, Annunziato F, Lazzeri E, Giannini S, Cosmi L et al (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. J Exp Med 197(11):1537–1549PubMedPubMedCentralCrossRefGoogle Scholar
- 10.Koizumi K, Hojo S, Akashi T, Yasumoto K, Saiki I (2007) Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune response. Cancer Sci 98(11):1652–1658PubMedCrossRefGoogle Scholar
- 11.Zhang R, Tian L, Chen LJ, Xiao F, Hou JM, Zhao X et al (2006) Combination of MIG (CXCL9) chemokine gene therapy with low-dose cisplatin improves therapeutic efficacy against murine carcinoma. Gene Ther 13(17):1263–1271PubMedCrossRefGoogle Scholar
- 12.Addison CL, Arenberg DA, Morris SB, Xue YY, Burdick MD, Mulligan MS et al (2000) The CXC chemokine, monokine induced by interferon-gamma, inhibits non-small cell lung carcinoma tumor growth and metastasis. Human Gene Ther 11(2):247–261CrossRefGoogle Scholar
- 13.Sharma S, Stolina M, Luo J, Strieter RM, Burdick M, Zhu LX et al (2000) Secondary lymphoid tissue chemokine mediates T cell-dependent antitumor responses in vivo. J Immunol 164(9):4558–4563PubMedCrossRefGoogle Scholar
- 14.Sharma S, Yang SC, Hillinger S, Zhu LX, Huang M, Batra RK et al (2003) SLC/CCL21-mediated anti-tumor responses require IFNgamma, MIG/CXCL9 and IP-10/CXCL10. Mol Cancer 2:22PubMedPubMedCentralCrossRefGoogle Scholar
- 15.Pan J, Burdick MD, Belperio JA, Xue YY, Gerard C, Sharma S et al (2006) CXCR3/CXCR3 ligand biological axis impairs RENCA tumor growth by a mechanism of immunoangiostasis. J Immunol 176(3):1456–1464PubMedCrossRefGoogle Scholar
- 16.Patil RS, Shah SU, Shrikhande SV, Goel M, Dikshit RP, Chiplunkar SV (2016) IL17 producing gammadeltaT cells induce angiogenesis and are associated with poor survival in gallbladder cancer patients. Int J Cancer 139(4):869–881PubMedCrossRefGoogle Scholar
- 17.Tan S, Wang K, Sun F, Li Y, Gao Y (2018) CXCL9 promotes prostate cancer progression through inhibition of cytokines from T cells. Mol Med Rep 18(2):1305–1310PubMedPubMedCentralGoogle Scholar
- 18.Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell. 127(4):679–695PubMedCrossRefGoogle Scholar
- 19.Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME et al (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410(6824):50–56PubMedCrossRefGoogle Scholar
- 20.Amatschek S, Lucas R, Eger A, Pflueger M, Hundsberger H, Knoll C et al (2011) CXCL9 induces chemotaxis, chemorepulsion and endothelial barrier disruption through CXCR3-mediated activation of melanoma cells. Br J Cancer 104(3):469–479PubMedCrossRefGoogle Scholar
- 21.Li Z, Liu J, Li L, Shao S, Wu J, Bian L et al (2018) Epithelial mesenchymal transition induced by the CXCL9/CXCR3 axis through AKT activation promotes invasion and metastasis in tongue squamous cell carcinoma. Oncol Rep 39(3):1356–1368PubMedGoogle Scholar
- 22.Bronger H, Karge A, Dreyer T, Zech D, Kraeft S, Avril S et al (2017) Induction of cathepsin B by the CXCR3 chemokines CXCL9 and CXCL10 in human breast cancer cells. Oncol Lett 13(6):4224–4230PubMedPubMedCentralCrossRefGoogle Scholar
- 23.Ding Q, Xia Y, Ding S, Lu P, Sun L, Liu M (2016) An alternatively spliced variant of CXCR3 mediates the metastasis of CD133+ liver cancer cells induced by CXCL9. Oncotarget 7(12):14405–14414PubMedPubMedCentralCrossRefGoogle Scholar
- 24.Hu S, Li L, Yeh S, Cui Y, Li X, Chang HC et al (2015) Infiltrating T cells promote prostate cancer metastasis via modulation of FGF11→miRNA-541→androgen receptor (AR)→MMP9 signaling. Mol Oncol 9(1):44–57PubMedCrossRefGoogle Scholar
- 25.Chow MT, Ozga AJ, Servis RL, Frederick DT, Lo JA, Fisher DE et al (2019) Intratumoral activity of the CXCR3 chemokine system is required for the efficacy of anti-PD-1 therapy. Immunity 50(6):1498–1512.e5PubMedPubMedCentralCrossRefGoogle Scholar
- 26.Spaks A (2017) Role of CXC group chemokines in lung cancer development and progression. J Thoracic Dis 9:S164–SS71CrossRefGoogle Scholar
- 27.Cao Y, Huang H, Wang Z, Zhang G (2017) The inflammatory CXC chemokines, GROalpha(high), IP-10(low), and MIG(low), in tumor microenvironment can be used as new indicators for non-small cell lung cancer progression. Immunol Invest 46(4):361–374PubMedCrossRefGoogle Scholar
- 28.Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M et al (2010) Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28(1):105–113PubMedCrossRefGoogle Scholar
- 29.Zhi W, Ferris D, Sharma A, Purohit S, Santos C, He M et al (2014) Twelve serum proteins progressively increase with disease stage in squamous cell cervical cancer patients. Int J Gynecol Cancer 24(6):1085–1092PubMedCrossRefGoogle Scholar
- 30.Zhang M, Chun L, Sandoval V, Graor H, Myers J, Nthale J et al (2018) Systemic administration of beta-glucan of 200 kDa modulates melanoma microenvironment and suppresses metastatic cancer. Oncoimmunology 7(2):e1387347PubMedCrossRefGoogle Scholar
- 31.Proost P, Verpoest S, Van de Borne K, Schutyser E, Struyf S, Put W et al (2004) Synergistic induction of CXCL9 and CXCL11 by Toll-like receptor ligands and interferon-gamma in fibroblasts correlates with elevated levels of CXCR3 ligands in septic arthritis synovial fluids. J Leukocyte Biol 75(5):777–784PubMedCrossRefGoogle Scholar
- 32.Doorduijn EM, Sluijter M, Salvatori DC, Silvestri S, Maas S, Arens R et al (2017) CD4(+) T cell and NK cell interplay key to regression of MHC Class I(low) tumors upon TLR7/8 agonist therapy. Cancer Immunol Res 5(8):642–653PubMedCrossRefGoogle Scholar
- 33.Shimauchi T, Sugita K, Nishio D, Isoda H, Abe S, Yamada Y et al (2008) Alterations of serum Th1 and Th2 chemokines by combination therapy of interferon-gamma and narrowband UVB in patients with mycosis fungoides. J Dermatol Sci 50(3):217–225PubMedCrossRefGoogle Scholar
- 34.Hong M, Puaux AL, Huang C, Loumagne L, Tow C, Mackay C et al (2011) Chemotherapy induces intratumoral expression of chemokines in cutaneous melanoma, favoring T-cell infiltration and tumor control. Cancer Res 71(22):6997–7009PubMedCrossRefGoogle Scholar
- 35.Hu JM, Bernatchez C, Xia XQ, Xu ZH, Hwu P, Li SL (2016) CXCL9, CXCL10 and IFN gamma favor the accumulation of infused T cells in tumors following IL-12 plus doxorubicin treatment. J Immunol 196:212.1CrossRefGoogle Scholar
- 36.Kershaw MH, Wang G, Westwood JA, Pachynski RK, Tiffany HL, Marincola FM et al (2002) Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2. Human Gene Ther 13(16):1971–1980CrossRefGoogle Scholar
- 37.Wennerberg E, Kremer V, Childs R, Lundqvist A (2015) CXCL10-induced migration of adoptively transferred human natural killer cells toward solid tumors causes regression of tumor growth in vivo. Cancer Immunol Immunother 64(2):225–235PubMedCrossRefGoogle Scholar
- 38.Wendel M, Galani IE, Suri-Payer E, Cerwenka A (2008) Natural killer cell accumulation in tumors is dependent on IFN-gamma and CXCR3 ligands. Cancer Res 68(20):8437–8445PubMedCrossRefGoogle Scholar
- 39.Kremer V, Ligtenberg MA, Zendehdel R, Seitz C, Duivenvoorden A, Wennerberg E et al (2017) Genetic engineering of human NK cells to express CXCR2 improves migration to renal cell carcinoma. J Immunother Cancer 5(1):73PubMedPubMedCentralCrossRefGoogle Scholar