Genotype of Immunologically Hot or Cold Tumors Determines the Antitumor Immune Response and Efficacy by Fully Virulent Retargeted oHSV

Viruses

Mara Sanapo¹  Daniela Bressanin¹  Gabriella Campadelli-Fiume¹  Federico Parenti¹  Andrea Vannini¹  Tatiana Gianni¹  Valerio Leoni¹  Catia Barboni²  Anna Zaghini² 

[1] Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40126 Bologna, Italy;Department of Veterinary Medical Sciences, University of Bologna, 40126 Bologna, Italy;

关键词: oncolytic virus;    oncolytic herpes simplex virus;    retargeting;    HER2;    tumor genotype;    vaccination;   

DOI  :  10.3390/v13091747

来源: DOAJ

【 摘 要 】

We report on the efficacy of the non-attenuated HER2-retargeted oHSV named R-337 against the immunologically hot CT26-HER2 tumor, and an insight into the basis of the immune protection. Preliminarily, we conducted an RNA immune profiling and immune cell content characterization of CT26-HER2 tumor in comparison to the immunologically cold LLC1-HER2 tumor. CT26-HER2 tumor was implanted into HER2-transgenic BALB/c mice. Hallmarks of R-337 effects were the protection from primary tumor, long-term adaptive vaccination directed to both HER2 and CT26-wt cell neoantigens. The latter effect differentiated R-337 from OncoVEXGM-CSF. As to the basis of the immune protection, R-337 orchestrated several changes to the tumor immune profile, which cumulatively reversed the immunosuppression typical of this tumor (graphical abstract). Thus, Ido1 (inhibitor of T cell anticancer immunity) levels and T regulatory cell infiltration were decreased; Cd40 and Cd27 co-immunostimulatory markers were increased; the IFNγ cascade was activated. Of note was the dampening of IFN-I response, which we attribute to the fact that R-337 is fully equipped with genes that contrast the host innate response. The IFN-I shut-down likely favored viral replication and the expression of the mIL-12 payload, which, in turn, boosted the antitumor response. The results call for a characterization of tumor immune markers to employ oncolytic herpesviruses more precisely.

【 授权许可】

Unknown