Abstract
Fusokines are proteins formed by the fusion of two cytokines. They have greater bioavailability and therapeutic potential than individual cytokines or a combination of different cytokines. Interferon-gamma-inducible protein 10 (CXCL10) and lymphotactin (XCL1) are members of the chemotactic family of cytokines, which induce tumor regression by eliciting immune-system cell chemotaxis. We engineered a replication-deficient adenoviral system expressing CXCL10/XCL1 fusokine (Ad FIL) and assessed its chemotactic response in vitro and in vivo. The CXCL10/XCL1 fusokine elicited a greater chemotactic effect in IL-2 stimulated lymphocytes than individual or combined cytokines in vitro. CXCL10/XCL1 fusokine biological activity was demonstrated in vivo by intratumoral chemoattraction of CXCR3+ cells. Thus, this novel CXCL10/XCL1 fusokine may represent a potential tool for gene therapy treatment of cancer and other illnesses that require triggering immune-system cell recruitment.
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References
Cairns CM, Gordon JR, Li F et al (2001) Lymphotactin expression by engineered myeloma cells drives tumor regression: mediation by CD4+ and CD8+ T cells and neutrophils expressing XCR1 receptor. J Immunol Baltim Md 1950 167:57–65
Cheng W-F, Hung C-F, Chai C-Y et al (2001) Tumor-specific immunity and antiangiogenesis generated by a DNA vaccine encoding calreticulin linked to a tumor antigen. J Clin Invest 108:669–678
Dufour JH, Dziejman M, Liu MT et al (2002) IFN-γ-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking. J Immunol 168:3195–3204. doi:10.4049/jimmunol.168.7.3195
Gattinoni L, Powell DJ, Rosenberg SA, Restifo NP (2006) Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 6:383–393
Gomez-Gutierrez JG, Elpek KG, de Oca-Luna RM et al (2007) Vaccination with an adenoviral vector expressing calreticulin-human papillomavirus 16 E7 fusion protein eradicates E7 expressing established tumors in mice. Cancer Immunol Immunother CII 56:997–1007
Gooden MJM, de Bock GH, Leffers N et al (2011) The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer 105:93–103
Huang H, Xiang J (2004) Synergistic effect of lymphotactin and interferon gamma-inducible protein-10 transgene expression in T-cell localization and adoptive T-cell therapy of tumors. Int J Cancer J Int Cancer 109:817–825
Källberg M, Wang H, Wang S et al (2012) Template-based protein structure modeling using the RaptorX web server. Nat Protoc 7:1511–1522
Lei Y, Takahama Y (2012) XCL1 and XCR1 in the immune system. Microbes Infect Inst Pasteur 14:262–267
Proudfoot AEI (2002) Chemokine receptors: multifaceted therapeutic targets. Nat Rev Immunol 2:106–115
Raman D, Baugher PJ, Thu YM, Richmond A (2007) Role of chemokines in tumor growth. Cancer Lett 256:137–165
Russell HV, Strother D, Mei Z et al (2007) Phase I trial of vaccination with autologous neuroblastoma tumor cells genetically modified to secrete IL-2 and lymphotactin. J Immunother Hagerstown Md 1997 30:227–233
Wang P, Yang X, Xu W et al (2010) Integrating individual functional moieties of CXCL10 and CXCL11 into a novel chimeric chemokine leads to synergistic antitumor effects: a strategy for chemokine-based multi-target-directed cancer therapy. Cancer Immunol Immunother CII 59:1715–1726
Wang X, Lu X-L, Zhao H-Y et al (2013) A novel recombinant protein of IP10-EGFRvIIIscFv and CD8(+) cytotoxic T lymphocytes synergistically inhibits the growth of implanted glioma in mice. Cancer Immunol Immunother CII 62:1261–1272
Wansom D, Light E, Thomas D et al (2012) Infiltrating lymphocytes and human papillomavirus-16 associated oropharynx cancer. Laryngoscope 122:121–127
Wennerberg E, Kremer V, Childs R, Lundqvist A (2014) CXCL10-induced migration of adoptively transferred human natural killer cells toward solid tumors causes regression of tumor growth in vivo. Cancer Immunol Immunother CII. doi:10.1007/s00262-014-1629-5
Williams P, Galipeau J (2011) GM-CSF–based fusion Cytokines as ligands for immune modulation. J Immunol 186:5527–5532
Yang X, Chu Y, Wang Y et al (2006) Targeted in vivo expression of IFN-gamma-inducible protein 10 induces specific antitumor activity. J Leukoc Biol 80:1434–1444
Zhang J, Zhou Z, Wang C et al (2011) Reduced tumorigenesis of EG7 after interleukin-10 gene transfer and enhanced efficacy in combination with intratumorally injection of adenovirus-mediated lymphotactin and the underlying mechanism. Cancer Immunol Immunother CII 60:559–573
Acknowledgments
This work was supported by Programa de Apoyo a la Investigación en Ciencia y Tecnología (PAICYT) No. SA381-10 from the UANL, and by ConsejoNacional de Ciencia y Tecnología (CONACYT) Grant No. CB-10-158509. YESL and JJPT were recipients of scholarships from CONACYT.
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The authors declare that they have no conflict of interest.
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Sanchez-Lugo, Y.E., Perez-Trujillo, J.J., Gutierrez-Puente, Y. et al. CXCL10/XCL1 fusokine elicits in vitro and in vivo chemotaxis. Biotechnol Lett 37, 779–785 (2015). https://doi.org/10.1007/s10529-014-1746-4
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DOI: https://doi.org/10.1007/s10529-014-1746-4