Comparison of the anti-tumor activity of native, secreted, and membrane-bound LIGHT in mouse tumor models.
The TNF superfamily member LIGHT has potent anti-tumor activity through direct cytotoxicity and activation of the immune response, and is a promising candidate for cancer therapy. Natively, LIGHT exists as both a membrane-anchored form and a proteolytically processed, secreted form. However, the strength of the anti-tumor activity of each form of LIGHT has not been well defined. Here, to identify the optimal form of LIGHT for cancer gene therapy, we constructed fiber-mutant adenovirus vectors (AdRGD) encoding native full-length LIGHT (LIGHT/FL), stably membrane-anchored LIGHT (LIGHT/mem), and fully secreted LIGHT (LIGHT/sec). We then compared the anti-tumor effects of the different forms of LIGHT in mice by intratumoral injection of each AdRGD. We demonstrated that intratumoral injection of AdRGD-LIGHT/sec provided greater tumor suppression than AdRGD-LIGHT/FL, although this effect did not reach statistical significance. By comparison, AdRGD-LIGHT/mem had negligible anti-tumor activity. We also demonstrated that more CD4+ and CD8+ T cells accumulated inside tumors treated in vivo with AdRGD-LIGHT/sec than in tumors treated with AdRGD-LIGHT/FL or AdRGD-LIGHT/mem. These results suggest that the secreted form of LIGHT might be the optimal form for cancer gene therapy.
Laboratory of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
Tomohiro
T
Morishige
Yasuo
Y
Yoshioka
Aya
A
Tanabe
Xinglei
X
Yao
Hiroyuki
H
Mizuguchi
Shin-ichi
S
Tsunoda
Yasuo
Y
Tsutsumi
Yohei
Y
Mukai
Naoki
N
Okada
Shinsaku
S
Nakagawa
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D015316:Genetic Therapy; D005822:Genetic Vectors; D019073:HT29 Cells; D006801:Humans; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008565:Membrane Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D015202:Protein Engineering; D047368:Tumor Burden / Q000235:genetics; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D008565:Membrane Proteins; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14