Metformin enhances the antitumor activity of oncolytic herpes simplex virus HF10 (canerpaturev) in a pancreatic cell cancer subcutaneous model

• Published in: Scientific reports Vol. 12; no. 1; p. 21570
• Main Authors: Abdelmoneim, Mohamed, Eissa, Ibrahim Ragab, Aboalela, Mona Alhussein, Naoe, Yoshinori, Matsumura, Shigeru, Sibal, Patricia Angela, Bustos-Villalobos, Itzel, Tanaka, Maki, Kodera, Yasuhiro, Kasuya, Hideki
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 13.12.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Antidiabetics; Antitumor activity; Cancer; Cancer immunotherapy; CD103 antigen; CD44 antigen; CD8 antigen; Cell differentiation; Cell Line, Tumor; Cytotoxicity; Dendritic cells; Diabetes mellitus; Herpes simplex; Herpes viruses; Herpesvirus 1, Human; Humans; Immunogenicity; Immunoregulation; Immunotherapy; Lymph nodes; Lymphocytes T; Lysis; Metformin; Metformin - pharmacology; Mice; Oncolysis; Oncolytic Virotherapy; Oncolytic Viruses; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - therapy; PD-1 protein; Tumors; Viruses
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-25065-w

Oncolytic virus (OV) therapy is a promising cancer immunotherapy, especially for cold tumors by inducing the direct lysis of cancer cells and initiation of potent antitumor response. Canerpaturev (C-REV) is an attenuated oncolytic herpes simplex virus-1, which demonstrated a potent antitumor effect in various preclinical models when used either alone or combined. Metformin is a commonly prescribed antidiabetic drug that demonstrated a potent immune modulator effect and antitumor response. We combined C-REV with metformin in a low immunogenic bilateral murine tumor model to enhance C-REV's antitumor efficacy. In vitro, metformin does not enhance the C-REV cell cytotoxic effect. However, in in vivo model, intratumoral administration of C-REV with the systemic administration of metformin led to synergistic antitumor effect on both sides of tumor and prolonged survival. Moreover, combination therapy increased the effector CD44 CD8 PD1 subset and decreased the proportion of terminally-differentiated CD103 KLRG-1 T-regulatory cells on both sides of tumor. Interestingly, combination therapy efficiently modulates conventional dendritic cells type-1 (cDC1) on tumors, and tumor-drained lymph nodes. Our findings suggest that combination of C-REV and metformin enhances systemic antitumor immunity. This study may provide insights into the mechanism of action of OV therapy plus metformin combination against various tumor models.