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

• Published in: Scientific reports 2022-12, Vol.12 (1), p.21570-21570, Article 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: Article
• Language: English
• Subjects: 631/67/1059/2325; 631/67/580; 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; Humanities and Social Sciences; Humans; Immunogenicity; Immunoregulation; Immunotherapy; Lymph nodes; Lymphocytes T; Lysis; Metformin; Metformin - pharmacology; Mice; multidisciplinary; Oncolysis; Oncolytic Virotherapy; Oncolytic Viruses; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - therapy; PD-1 protein; Science; Science (multidisciplinary); 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.