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.
Morishige
Tomohiro
T
Laboratory of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
Yoshioka
Yasuo
Y
Tanabe
Aya
A
Yao
Xinglei
X
Mizuguchi
Hiroyuki
H
Tsunoda
Shin-ichi
S
Tsutsumi
Yasuo
Y
Mukai
Yohei
Y
Okada
Naoki
N
Nakagawa
Shinsaku
S
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