Modification of dendritic cells with interferon-γ-inducible protein-10 gene to enhance vaccine potency

Background Dendritic cell (DC)-based vaccines have become a promising modality in cancer immunotherapy. However, their ability to initiate tumor antigen-specific T cell immunity is limited in various negative-feedback mechanisms. The rapid down-regulation of chemokines, such as the interferon inducible protein of 10 kDa (IP-10), which chemoattracts activated antigen-specific CD8(+) T cells, would represent negative-feedback regulation. Therefore, we attempted to improve DC vaccine potency by introducing the IP-10 gene retrovirally aiming to replenish the chemoattractive activity of DCs. Methods We introduced IP-10 gene into DC2.4 cells, referred to as DC-IP10, using a retroviral system. Nonsecretable mIP-10-expressing DCs (DC-mIP10) were also prepared to evaluate the effects of secretion in IP-10-mediated modulation of DC biology. Additionally, in vitro and in vivo activation of antigen-specific T lymphocytes and in vivo anti-tumor effects induced by DC-IP10 or DC-mIP10 were determined. Results The modification of DC2.4 cells with the IP-10 gene resulted in the secretion of functionally chemoattractive IP-10 and, unexpectedly, a significant up-regulation of surface expression in co-stimulatory molecules, such as CD40 and CD80, compared to that of DCs with vector control (DC-no insert). DC-mIP10 also displayed the partially matured phenotypes but failed to recruit antigen-specific T cells in an in vitro cell culture system. Consistently, DC-IP10 generated more tumor antigen-specific CD8+ T cells and stronger anti-tumor effects in vaccinated mice than did control DCs and DC-mIP10. Conclusions The results obtained provide the groundwork for a future clinical translation of the chemokine-based genetic modification of DCs to increase their vaccine potency. Copyright (C) 2009 John Wiley & Sons, Ltd.Qian C, 2007, BLOOD, V109, P3308, DOI 10.1182/blood-2006-08-040337Kang TH, 2007, INT J CANCER, V120, P1696, DOI 10.1002/ijc.22377Kang TH, 2007, CANCER RES, V67, P802, DOI 10.1158/0008-5472.CAN-06-2638Reddy ST, 2006, TRENDS IMMUNOL, V27, P573, DOI 10.1016/j.it.2006.10.005Kang TH, 2006, IMMUNOL LETT, V106, P126, DOI 10.1016/j.imlet.2006.05.004Klebanoff CA, 2006, IMMUNOL REV, V211, P214Krathwohl MD, 2006, VACCINE, V24, P2987, DOI 10.1016/j.vaccine.2005.11.032Christensen JE, 2006, J IMMUNOL, V176, P4235Cronin J, 2005, CURR GENE THER, V5, P387Kim TW, 2005, CANCER RES, V65, P309Hsieh CJ, 2004, VACCINE, V22, P3993, DOI 10.1016/j.vaccine.2004.03.057Yang JM, 2004, MOL THER, V9, P846, DOI 10.1016/j.ymthe.2004.01.010Kim TW, 2004, GENE THER, V11, P336, DOI 10.1038/sj.gt.3302164Lin CT, 2003, MOL THER, V8, P559, DOI 10.1016/S1525-0016(03)00238-7Kim TW, 2003, J IMMUNOL, V171, P2970Meier CA, 2003, CYTOKINE, V21, P43, DOI 10.1016/S1043-4666(02)00491-XPenna G, 2002, HUM IMMUNOL, V63, P1164Nishimura M, 2002, J IMMUNOL, V168, P6173Dufour JH, 2002, J IMMUNOL, V168, P3195Fukada K, 2002, J IMMUNOL, V168, P2225Idzko M, 2002, FASEB J, V16, P625, DOI 10.1096/fj.01-0625fjeKawai T, 2001, J IMMUNOL, V167, P5887Tourkova IL, 2001, IMMUNOL LETT, V78, P75Pertl U, 2001, J IMMUNOL, V166, P6944Moser B, 2001, NAT IMMUNOL, V2, P123Chen CH, 2000, VACCINE, V18, P2015Gangur V, 1998, FASEB J, V12, P705Luster AD, 1998, NEW ENGL J MED, V338, P436LI X, 1998, J HUMAN VIROL, V1, P346Shen ZH, 1997, J IMMUNOL, V158, P2723Sgadari C, 1996, P NATL ACAD SCI USA, V93, P13791Lin KY, 1996, CANCER RES, V56, P21STEINMAN RM, 1991, ANNU REV IMMUNOL, V9, P271KAPLAN G, 1987, J EXP MED, V166, P1098