E1A-engineered human umbilical cord mesenchymal stem cells as carriers and amplifiers for adenovirus suppress hepatocarcinoma in mice

The immunosuppressive tumor microenvironment limits the application of adoptive immunotherapy for solid tumors. Hypoxia is closely associated with the formation of the immunosuppressive tumor microenvironment. Hypoxia‑inducible factor‑1 (HIF‑1) is an oxygen‑sensitive transcriptional activator that drives the transcription of several immunosuppressive molecules. In addition, previous studies confirmed that rhein downregulated the expression of HIF‑1α, a subunit of HIF‑1, in pancreatic cancer cells. The present study established correlations between mRNA expression levels of HIF‑1α and six immunosuppressive molecules in colorectal cancer (CRC) tissue samples. This study examined the effect of rhein on the expression levels of HIF‑1α and six immunosuppressive molecules in CRC cell lines under hypoxic conditions by western blot analysis and reverse transcription‑quantitative polymerase chain reaction. This study demonstrated that rhein downregulated the expression of HIF‑1α and immunosuppressive molecules in CRC cells under hypoxic conditions. In addition, the present study analyzed the cytotoxicity of peripheral blood lymphocytes in vitro using a non‑toxic cytotoxicity assay. This study demonstrated that in vitro, rhein enhanced the cytotoxicity of effector lymphocytes toward tumor cells under hypoxic conditions, and therefore rhein may be used in combination with effector lymphocytes for the treatment of CRC.

We previously established a hepatocellular carcinoma (HCC) targeting system of conditionally replicative adenovirus (CRAd) delivered by human umbilical cord-derived mesenchymal stem cells (HUMSCs). However, this system needed to be developed further to enhance the antitumor effect and overcome the limitations caused by the alpha-fetoprotein (AFP) heterogeneity of HCC. In this study, a bispecific T cell engager (BiTE) targeting programmed death ligand 1 controlled by the human telomerase reverse transcriptase promoter was armed on the CRAd of the old system. It was demonstrated on orthotopic transplantation model mice that the new system had a better anti-tumor effect with no more damage to extrahepatic organs and less liver injury, and the infiltration and activation of T cells were significantly enhanced in the tumor tissues of the model mice treated with the new system. Importantly, we confirmed that the new system eliminated the AFP-negative cells on AFP heterogeneous tumor models efficiently. Conclusion: Compared with the old system, the new system provided a more effective and safer strategy against HCC.

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