CX3CL1 Signaling in the Tumor Microenvironment

  • Melissa J. ConroyEmail author
  • Joanne Lysaght
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1231)


CX3CL1 (Fractalkine) is a multifunctional inflammatory chemokine with a single receptor CX3CR1. The biological effects elicited by CX3CL1 on surrounding cells vary depending on a number of factors including its structure, the expression pattern of CX3CR1, and the cell type. For instance, the transmembrane form of CX3CL1 primarily serves as an adhesion molecule, but when cleaved to a soluble form, CX3CL1 predominantly functions as a chemotactic cytokine (Fig. 1.1). However, the biological functions of CX3CL1 also extend to immune cell survival and retention. The pro-inflammatory nature of CX3CR1-expressing immune cells place the CX3CL1:CX3CR1 axis as a central player in multiple inflammatory disorders and position this chemokine pathway as a potential therapeutic target. However, the emerging role of this chemokine pathway in the maintenance of effector memory cytotoxic T cell populations implicates it as a key chemokine in anti-viral and anti-tumor immunity, and therefore an unsuitable therapeutic target in inflammation. The reported role of CX3CL1 as a key regulator of cytotoxic T cell-mediated immunity is supported by several studies that demonstrate CX3CL1 as an important TIL-recruiting chemokine and a positive prognostic factor in colorectal, breast, and lung cancer. Such reports are conflicting with an overwhelming number of studies demonstrating a pro-tumorigenic and pro-metastatic role of CX3CL1 across multiple blood and solid malignancies.

This chapter will review the unique structure, function, and biology of CX3CL1 and address the diversity of its biological effects in the immune system and the tumor microenvironment. Overall, this chapter highlights how we have just scratched the surface of CX3CL1’s capabilities and suggests that further in-depth and mechanistic studies incorporating all CX3CL1 interactions must be performed to fully appreciate its role in cancer and its potential as a therapeutic target.


Chemokines CX3CL1 CX3CR1 Cancer Inflammation T cells Natural killer (NK) cells Tumor-associated macrophages (TAMs) Metastasis Tumor microenvironment Cell adhesion Migration 


  1. 1.
    Bazan JF et al (1997) A new class of membrane-bound chemokine with a CX3C motif. Nature 385(6617):640–644PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Fong AM et al (1998) Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow. J Exp Med 188(8):1413–1419PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Imai T et al (1997) Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell 91(4):521–530PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Garton KJ et al (2001) Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1). J Biol Chem 276(41):37993–38001PubMedPubMedCentralGoogle Scholar
  5. 5.
    Tsou CL, Haskell CA, Charo IF (2001) Tumor necrosis factor-alpha-converting enzyme mediates the inducible cleavage of fractalkine. J Biol Chem 276(48):44622–44626PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Conroy MJ et al (1867) Identifying a Novel Role for Fractalkine (CX3CL1) in Memory CD8+ T Cell Accumulation in the Omentum of Obesity-Associated Cancer Patients. Front Immunol 9:2018Google Scholar
  7. 7.
    Bottcher JP et al (2015) Functional classification of memory CD8(+) T cells by CX3CR1 expression. Nat Commun 6:8306PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    White GE et al (2014) Fractalkine promotes human monocyte survival via a reduction in oxidative stress. Arterioscler Thromb Vasc Biol 34(12):2554–2562PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Mionnet C et al (2010) CX3CR1 is required for airway inflammation by promoting T helper cell survival and maintenance in inflamed lung. Nat Med 16(11):1305–1312PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Shin MS et al (2015) DNA Methylation Regulates the Differential Expression of CX3CR1 on Human IL-7Ralphalow and IL-7Ralphahigh Effector Memory CD8+ T Cells with Distinct Migratory Capacities to the Fractalkine. J Immunol 195(6):2861–2869PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Landsman L et al (2009) CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival. Blood 113(4):963–972PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Nakayama T et al (2010) Eotaxin-3/CC chemokine ligand 26 is a functional ligand for CX3CR1. J Immunol 185(11):6472–6479PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Nishimura M et al (2002) Dual functions of fractalkine/CX3C ligand 1 in trafficking of perforin+/granzyme B+ cytotoxic effector lymphocytes that are defined by CX3CR1 expression. J Immunol 168(12):6173–6180PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Wada A et al (2015) Role of chemokine CX3CL1 in progression of multiple myeloma via CX3CR1 in bone microenvironments. Oncol Rep 33(6):2935–2939PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Corcione A, Ferretti E, Pistoia V (2012) CX3CL1/fractalkine is a novel regulator of normal and malignant human B cell function. J Leukoc Biol 92(1):51–58PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Liu P et al (2018) CX3CL1/fractalkine enhances prostate cancer spinal metastasis by activating the Src/FAK pathway. Int J Oncol 53(4):1544–1556PubMedPubMedCentralGoogle Scholar
  17. 17.
    Huang LY et al (2012) Fractalkine upregulates inflammation through CX3CR1 and the Jak-Stat pathway in severe acute pancreatitis rat model. Inflammation 35(3):1023–1030PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Lee YS et al (2018) CX3CR1 differentiates F4/80(low) monocytes into pro-inflammatory F4/80(high) macrophages in the liver. Sci Rep 8(1):15076PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Kitaura M et al (1999) Molecular cloning of a novel human CC chemokine (Eotaxin-3) that is a functional ligand of CC chemokine receptor 3. J Biol Chem 274(39):27975–27980PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Petkovic V et al (2004) Eotaxin-3/CCL26 is a natural antagonist for CC chemokine receptors 1 and 5. A human chemokine with a regulatory role. J Biol Chem 279(22):23357–23363PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Ogilvie P et al (2003) Eotaxin-3 is a natural antagonist for CCR2 and exerts a repulsive effect on human monocytes. Blood 102(3):789–794PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    El-Shazly AE et al (2013) Novel cooperation between CX3CL1 and CCL26 inducing NK cell chemotaxis via CX3CR1: a possible mechanism for NK cell infiltration of the allergic nasal tissue. Clin Exp Allergy 43(3):322–331PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Batool A et al (2018) A miR-125b/CSF1-CX3CL1/tumor-associated macrophage recruitment axis controls testicular germ cell tumor growth. Cell Death Dis 9(10):962PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Geismann C et al (2018) TRAIL/NF-kappaB/CX3CL1 mediated onco-immuno crosstalk leading to TRAIL resistance of pancreatic cancer cell lines. Int J Mol Sci 19:6CrossRefGoogle Scholar
  25. 25.
    Lavergne E et al (2003) Fractalkine mediates natural killer-dependent antitumor responses in vivo. Cancer Res 63(21):7468–7474PubMedPubMedCentralGoogle Scholar
  26. 26.
    Liang Y et al (2018) CX3CL1 involves in breast cancer metastasizing to the spine via the Src/FAK signaling pathway. J Cancer 9(19):3603–3612PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Liu W et al (2017) CX3CL1: a potential chemokine widely involved in the process spinal metastases. Oncotarget 8(9):15213–15219PubMedPubMedCentralGoogle Scholar
  28. 28.
    Marchesi F et al (2008) The chemokine receptor CX3CR1 is involved in the neural tropism and malignant behavior of pancreatic ductal adenocarcinoma. Cancer Res 68(21):9060–9069PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Stout MC et al (2018) Inhibition of CX3CR1 reduces cell motility and viability in pancreatic adenocarcinoma epithelial cells. Biochem Biophys Res Commun 495(3):2264–2269PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Tang J et al (2016) CX3CL1 increases invasiveness and metastasis by promoting epithelial-to-mesenchymal transition through the TACE/TGF-alpha/EGFR pathway in hypoxic androgen-independent prostate cancer cells. Oncol Rep 35(2):1153–1162PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Tardaguila M et al (2013) CX3CL1 promotes breast cancer via transactivation of the EGF pathway. Cancer Res 73(14):4461–4473PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Xin H et al (2005) Antitumor immune response by CX3CL1 fractalkine gene transfer depends on both NK and T cells. Eur J Immunol 35(5):1371–1380PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Nukiwa M et al (2006) Dendritic cells modified to express fractalkine/CX3CL1 in the treatment of preexisting tumors. Eur J Immunol 36(4):1019–1027PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Zeng Y et al (2005) Fractalkine gene therapy for neuroblastoma is more effective in combination with targeted IL-2. Cancer Lett 228(1–2):187–193PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Siddiqui I et al (2016) Enhanced recruitment of genetically modified CX3CR1-positive human T cells into Fractalkine/CX3CL1 expressing tumors: importance of the chemokine gradient. J Immunother Cancer 4:21PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Yan Y et al (2018) CX3CR1 identifies PD-1 therapy-responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy. JCI Insight 3:8CrossRefGoogle Scholar
  37. 37.
    Hyakudomi M et al (2008) Increased expression of fractalkine is correlated with a better prognosis and an increased number of both CD8+ T cells and natural killer cells in gastric adenocarcinoma. Ann Surg Oncol 15(6):1775–1782PubMedCrossRefGoogle Scholar
  38. 38.
    Ohta M et al (2005) The high expression of Fractalkine results in a better prognosis for colorectal cancer patients. Int J Oncol 26(1):41–47PubMedGoogle Scholar
  39. 39.
    Park MH, Lee JS, Yoon JH (2012) High expression of CX3CL1 by tumor cells correlates with a good prognosis and increased tumor-infiltrating CD8+ T cells, natural killer cells, and dendritic cells in breast carcinoma. J Surg Oncol 106(4):386–392PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Tsang JY et al (2013) CX3CL1 expression is associated with poor outcome in breast cancer patients. Breast Cancer Res Treat 140(3):495–504PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Schmall A et al (2015) Macrophage and cancer cell cross-talk via CCR2 and CX3CR1 is a fundamental mechanism driving lung cancer. Am J Respir Crit Care Med 191(4):437–447PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Liu J et al (2019) Increased CX3CL1 mRNA expression level is a positive prognostic factor in patients with lung adenocarcinoma. Oncol Lett 17(6):4877–4890PubMedPubMedCentralGoogle Scholar
  43. 43.
    Okuma A et al (2017) p16(Ink4a) and p21(Cip1/Waf1) promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis. Nat Commun 8(1):2050PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Obermajer N et al (2011) PGE(2)-induced CXCL12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Cancer Res 71(24):7463–7470PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Kalinski P (2012) Regulation of immune responses by prostaglandin E2. J Immunol 188(1):21–28PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Xu X et al (2012) High expression of CX3CL1/CX3CR1 axis predicts a poor prognosis of pancreatic ductal adenocarcinoma. J Gastrointest Surg 16(8):1493–1498PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Liu JF, Tsao YT, Hou CH (2017) Fractalkine/CX3CL1 induced intercellular adhesion molecule-1-dependent tumor metastasis through the CX3CR1/PI3K/Akt/NF-kappaB pathway in human osteosarcoma. Oncotarget 8(33):54136–54148PubMedPubMedCentralGoogle Scholar
  48. 48.
    Ren H et al (2013) The CX3CL1/CX3CR1 reprograms glucose metabolism through HIF-1 pathway in pancreatic adenocarcinoma. J Cell Biochem 114(11):2603–2611PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Su YC et al (2018) Differential impact of CX3CL1 on lung cancer prognosis in smokers and non-smokers. Mol Carcinog 57(5):629–639PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Staniland AA et al (2010) Reduced inflammatory and neuropathic pain and decreased spinal microglial response in fractalkine receptor (CX3CR1) knockout mice. J Neurochem 114(4):1143–1157PubMedPubMedCentralGoogle Scholar
  51. 51.
    Shah R et al (2011) Fractalkine is a novel human adipochemokine associated with type 2 diabetes. Diabetes 60(5):1512–1518PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Souza GR et al (2013) Fractalkine mediates inflammatory pain through activation of satellite glial cells. Proc Natl Acad Sci U S A 110(27):11193–11198PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Xueyao Y et al (2014) Circulating fractalkine levels predict the development of the metabolic syndrome. Int J Endocrinol 2014:715148PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Cefalu WT (2011) Fractalkine: a cellular link between adipose tissue inflammation and vascular pathologies. Diabetes 60(5):1380–1382PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Desalegn G, Pabst O (2019) Inflammation triggers immediate rather than progressive changes in monocyte differentiation in the small intestine. Nat Commun 10(1):3229PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Dorgham K et al (2009) An engineered CX3CR1 antagonist endowed with anti-inflammatory activity. J Leukoc Biol 86(4):903–911PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Erreni M et al (2016) The fractalkine-receptor axis improves human colorectal cancer prognosis by limiting tumor metastatic dissemination. J Immunol 196(2):902–914PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Renehan AG et al (2008) Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371(9612):569–578PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Conroy MJ et al (2016) Parallel profiles of inflammatory and effector memory T cells in visceral fat and liver of obesity-associated cancer patients. Inflammation 39(5):1729–1736PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Lysaght J et al (2011) T lymphocyte activation in visceral adipose tissue of patients with oesophageal adenocarcinoma. Br J Surg 98(7):964–974PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Conroy MJ et al (2016) CCR1 antagonism attenuates T cell trafficking to omentum and liver in obesity-associated cancer. Immunol Cell Biol 94(6):531–537PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Kavanagh ME et al (2019) Altered T cell migratory capacity in the progression from barrett oesophagus to oesophageal adenocarcinoma. Cancer Microenviron 12(1):57–66PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Shen F et al (2016) Novel small-molecule CX3CR1 antagonist impairs metastatic seeding and colonization of breast cancer cells. Mol Cancer Res 14(6):518–527PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Cancer Immunology and Immunotherapy Group, Department of SurgeryTrinity Translational Medicine Institute, Trinity College Dublin, St James’s HospitalDublin 8Ireland

Personalised recommendations