Oncolytic adenovirus coding for shedding-resistant MICA enhances immune responses against tumors.
Cancer Immunol Immunother
; 73(1): 5, 2024 Jan 05.
Article
in En
| MEDLINE
| ID: mdl-38180524
ABSTRACT
Cancer immunotherapies strive to overcome tumor-induced immune suppression and activate antitumor immune responses. Although cytotoxic T lymphocytes (CTLs) play a pivotal role in this process, natural killer (NK) cells have also demonstrated remarkable tumor-killing abilities, given their ability to discriminate tumor cells from normal cells and mediate specific antitumoral cytotoxicity. NK cells activation depends on a balance between activation and inhibition signals from several ligands/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 serves as a 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 ICOVIR15KK-MICAMut, an oncolytic adenovirus (OAdv) 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 OAdv promotes higher NK activation and killing capacity than the non-armed virus in vitro. In addition, the armed virus also demonstrated significant antitumor activity in immunodeficient mice in the presence of human PBMCs, indicating the activation of human NK cells. Finally, OAdv-MICA overexpression in immunocompetent tumor-bearing mice elicits tumor-specific immune response resulting in a greater tumor growth control.In summary, this study highlights the significance of NK cells in cancer immunotherapy and presents an innovative approach using a modified oncolytic virus to enhance NK cell activation and antitumor immune response. These findings suggest promising potential for future research and clinical applications.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Adenoviridae
/
NK Cell Lectin-Like Receptor Subfamily K
Limits:
Animals
/
Humans
Language:
En
Journal:
Cancer Immunol Immunother
/
Cancer immunol. immunother
/
Cancer immunology and immunotherapy
Journal subject:
ALERGIA E IMUNOLOGIA
/
NEOPLASIAS
/
TERAPEUTICA
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: