Oncolytic adenovirus encoding LIGHT (TNFSF14) inhibits tumor growth via activating anti-tumor immune responses in 4T1 mouse mammary tumor model in immune competent syngeneic mice

摘要

LIGHT, also known as tumor-necrosis factor (TNF) superfamily member 14 (TNFSF14), is predominantly expressed on activated immune cells and some tumor cells. LIGHT is a pivotal regulator both for recruiting and activating immune cells in the tumor lesions. In this study, we armed human telomerase reverse transcriptase (TERT) promoter controlled oncolytic adenovirus with LIGHT to generate rAd.Light. rAd.Light effectively transduced both human and mouse breast tumor cell lines in vitro, and expressed LIGHT protein on the surface of tumor cells. Both rAd.Null, and rAd.Light could replicate in human breast cancer cells, and produced cytotoxicity to human and mouse mammary tumor cells. rAd.Light induced apoptosis resulting in tumor cell death. Using a subcutaneous model of 4T1 cells in BALB/c mice, rAd.Light was delivered intratumorally to evaluate the anti-tumor responses. Both rAd.Light and rAd.Null significantly inhibited the tumor growth, but rAd.Light produced much stronger anti-tumor effects. Histopathological analysis showed the infiltration of T lymphocytes in the tumor tissues. rAd.Light also induced stronger cellular apoptosis than rAd.Null in the tumors. Interestingly, on day 15, compared to rAd.Null, there was a significant reduction of Tregs following rAd.Light treatment. rAd.Light significantly increased Th1 cytokine interleukin (IL)-2 expression, and reduced Th2 cytokines expression, such as transforming growth factor (TGF-) and IL-10 in the tumors. These results suggest rAd.Light induced activation of anti-tumor immune responses. In conclusion, rAd.Light produced anti-tumor effect in a subcutaneous model of breast cancer via inducing tumor apoptosis and evoking strong anti-tumor immune responses. Therefore, rAd.Light has great promise to be developed as an effective therapeutic approach for the treatment of breast cancer.