Skip to main content
SpringerLink
Log in

The Multifaceted Roles of CXCL9 Within the Tumor Microenvironment

  • Chapter
  • First Online:
Book cover Tumor Microenvironment

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1231))

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Vicari AP, Caux C (2002) Chemokines in cancer. Cytokine Growth Factor Rev 13(2):143–154

    Article  CAS  PubMed  Google Scholar 

  2. Vignali D, Kallikourdis M (2017) Improving homing in T cell therapy. Cytokine Growth Factor Rev 36:107–116

    Article  CAS  PubMed  Google Scholar 

  3. Groom JR, Luster AD (2011) CXCR3 ligands: redundant, collaborative and antagonistic functions. Immunol Cell Biol 89(2):207–215

    Article  CAS  PubMed  Google 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):552–558

    Article  CAS  PubMed  Google 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):885

    Article  CAS  PubMed  PubMed Central  Google 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 186:48.4

    Google Scholar 

  7. Kerbel RS (2008) Tumor angiogenesis. N Engl J Med 358(19):2039–2049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Keeley EC, Mehrad B, Strieter RM (2011) Chemokines as mediators of tumor angiogenesis and neovascularization. Exp Cell Res 317(5):685–690

    Article  CAS  PubMed  Google 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):1537–1549

    Article  CAS  PubMed  PubMed Central  Google 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):1652–1658

    Article  CAS  PubMed  Google 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):1263–1271

    Article  CAS  PubMed  Google 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):247–261

    Article  CAS  Google 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):4558–4563

    Article  CAS  PubMed  Google 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 2:22

    Article  PubMed  PubMed Central  Google 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):1456–1464

    Article  CAS  PubMed  Google 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):869–881

    Article  PubMed  Google 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):1305–1310

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell. 127(4):679–695

    Article  CAS  PubMed  Google 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):50–56

    Article  CAS  PubMed  Google 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):469–479

    Article  CAS  PubMed  Google 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):1356–1368

    CAS  PubMed  Google 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):4224–4230

    Article  CAS  PubMed  PubMed Central  Google 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):14405–14414

    Article  PubMed  PubMed Central  Google 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):44–57

    Article  CAS  PubMed  Google 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.e5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Spaks A (2017) Role of CXC group chemokines in lung cancer development and progression. J Thoracic Dis 9:S164–SS71

    Article  Google 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):361–374

    Article  CAS  PubMed  Google 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):105–113

    Article  CAS  PubMed  Google 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):1085–1092

    Article  PubMed  Google 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):e1387347

    Article  PubMed  Google 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):777–784

    Article  CAS  PubMed  Google 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):642–653

    Article  CAS  PubMed  Google 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):217–225

    Article  CAS  PubMed  Google 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):6997–7009

    Article  CAS  PubMed  Google 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 196:212.1

    Article  Google 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):1971–1980

    Article  CAS  Google 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):225–235

    Article  CAS  PubMed  Google 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):8437–8445

    Article  CAS  PubMed  Google 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):73

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

    Shi Yong Neo & Andreas Lundqvist

Authors
  1. Shi Yong Neo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andreas Lundqvist
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andreas Lundqvist .

Editor information

Editors and Affiliations

  1. Department of Radiology, Columbia University Medical Center, New York, NY, USA

    Alexander Birbrair

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Neo, S.Y., Lundqvist, A. (2020). The Multifaceted Roles of CXCL9 Within the Tumor Microenvironment. In: Birbrair, A. (eds) Tumor Microenvironment. Advances in Experimental Medicine and Biology, vol 1231. Springer, Cham. https://doi.org/10.1007/978-3-030-36667-4_5

Download citation

Publish with us

Policies and ethics

Search

Navigation