Natural killer (NK) cell-mediated cancer immunotherapy has grown significantly over the past two decades. NK cells activation depends in a balance of activation and inhibition signals from several ligand/receptors. Among them, MICA/NKG2D axis is a master regulator of NK activation. MHC class I chain-related polypeptide A (MICA) expression is upregulated by many tumor cell lines and primary tumors and serve as ligand for the activating NK group 2D (NKG2D) receptor on NK cells and subpopulations of T cells. However, cancer cells can cleave MICA, making it soluble and de-targeting tumor cells from NK cells, leading to tumor immune escape.

In this study, we present ICOVIR15K.6.7/19K-MICAMut, an OAd armed with a transgene encoding a non-cleavable MICA to promote NK-mediated cell-killing capacity and activate the immune response against cancer cells. We first demonstrated the correct MICA overexpression from infected cells. Moreover, our MICA-expressing OAd promotes higher NK activation and killing capacity than the non-armed virus in vitro. In addition, OAd-MICA overexpression in immunocompetent tumor-bearing mice elicits tumor-specific immune response resulting in a greater tumor growth control. Finally, the armed virus also demonstrated significant antitumor activity in immunodeficient mice in the presence of human PBMCs, indicating the activation of human NK cells.

Overall, our findings suggest that the use of an oncolytic adenovirus armed with MICA represents a promising approach to combine virotherapy and immunotherapy against cancer.