Effects of immunotherapy of IL-6 and IL-15 plasmids on transmissible venereal tumor in beagles.
Canine transmissible venereal tumor (CTVT) is a tumor with low MHC antigen expression and is an ideal tumor model for studying the interactions between host immunity and cancer cells. CTVTs produce high concentrations of TGF-beta to hamper the host immune responses and facilitate their growth progression. However, during the later stages of tumor progression, tumor-infiltrating lymphocytes secrete IL-6. This cytokine antagonizes TGF-beta and restores the IFN-gamma activities in promoting MHC antigen expression, and the NK cytotoxicity that has been repressed by TGF-beta is also activated. In this study, we applied combinatory treatment of IL-6 plasmid and IL-15 plasmid (pIL-6/pIL-15) to CTVT-bearing beagles. IL-6 was used as an anti-TGF-beta cytokine; IL-15 was used to promote NK- and CTVT-specific cytotoxicity. After intratumoral pIL-6/pIL-15 delivery mediated by electroporation, MHC antigen expression on CTVT cells was dramatically increased from in less than 5.9% to up to 34% of the tumor cells. The proportion of CD8(+) T cells infiltrating the tumor was also significantly elevated from 6.96+/-0.23% to 21.63+/-5.40%. In addition, the tumor-specific cytotoxicity was enhanced along with a marked increase in tumor-specific IFN-gamma-producing cells. These immune responses are believed to be the important forces driving the tumor towards regression. The results indicate that pIL-6/pIL-15 combinatory immunotherapy may facilitate a promising and effective means of treating tumors.
Chou
Pei-Chung
PC
Animal Cancer Research Center, Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan, ROC.
Chuang
Tien-Fu
TF
Jan
Tong-Rong
TR
Gion
Hsin-Chan
HC
Huang
Yi-Chun
YC
Lei
Han-Jon
HJ
Chen
Win-Yin
WY
Chu
Rea-Min
RM
D000818:Animals; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004283:Dog Diseases / Q000276:immunology / Q000628:therapy*; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay / Q000662:veterinary; D005434:Flow Cytometry / Q000662:veterinary; D006649:Histocompatibility Antigens / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000379:methods / Q000662:veterinary*; D007371:Interferon-gamma / Q000276:immunology; D019409:Interleukin-15 / Q000097:blood / Q000235:genetics / Q000276:immunology*; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D010957:Plasmids / Q000235:genetics; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology; D014685:Venereal Tumors, Veterinary / Q000276:immunology / Q000628:therapy*
D006649:Histocompatibility Antigens; D019409:Interleukin-15; D015850:Interleukin-6; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma