Abstract 1471: Short hairpin RNA-expressing oncolytic adenovirus-mediated inhibition of PDL1 significantly suppresses human cancer cell growth

Abstract

Abstract In cancer immunotherapy, it is known that aberrant expression of immune checkpoint proteins in tumor cells and their resulting immunosuppression in surrounding tumor microenviroment and even in whole immune system represent the crucial limiting factors toward successful cancer treatment. Multiple studies evidenced that oncolytic viruses carrying biological molecule including cytokines, shRNAs and miRNAs relieve or attenuate immunosuppression, and may be a promising way toward curing tumor. In this study we generated an oncolytic adenovirus with expression of shRNA targeting human PDL1. The adenovirus exhibited proliferation activity more than two orders of magnitude higher in human cancer cells than in human normal primary cells. Western blot showed significantly decreased expressing levels of PDL1 protein in human cancer cells upon infection of the PDL1 shRNA expressing-oncolytic virus. FACS assay also showed decreased expression levels of PDL1 on the cell membrane after the infection of same viruses. In vivo experiments in two different genetic backgrounds mouse model <NOD-SCID mice and BALBC nude mice> demonstrated that the PDL1 shRNA expressing adenoviruses lysed the majority of the tumor cells derived from HCT116 colorectal cancer cells that were subcutaneously inoculated. Moreover, the adenoviruses downregulated PDL1 expression levels within the HCT116 colon cell-derived tumor cells, remarkably attenuated immunosuppression surrounding the HCT116 tumor. Consisted with these observations, TIL cell counts in the tumors derived from mice with shRNA expressing oncolytic adenovirus treatment were significantly higher than that from mice in other control groups. The growth of HCT116 colon cell-derived tumor in mice with oncolytic adenovirus treatment was greatly inhibited for a longer period compared with that in mice in other control groups. The oncolytic adenovirus described in this study features highly selective amplification in human tumor cells versus normal cells and inhibition of PDL1 expression in tumor cells, therefore it may be important toward developing novel method for cancer therapy. Citation Format: Jipo Sheng, Xue Wang, Xiaoming Dong, Jin Fu, Sanmao Kang, Fang Hu. Short hairpin RNA-expressing oncolytic adenovirus-mediated inhibition of PDL1 significantly suppresses human cancer cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1471.