S-1 facilitates canerpaturev (C-REV)-induced antitumor efficacy in a triple-negative breast cancer model

• Published in: Nagoya journal of medical science 2021-11, Vol.83 (4), p.683-696
• Main Authors: Miyajima, Noriyuki, Ragab Eissa, Ibrahim, Abdelmoneim, Mohamed, Naoe, Yoshinori, Ichinose, Toru, Matsumura, Shigeru, Bustos-Villalobos, Itzel, Mukoyama, Nobuaki, Morimoto, Daishi, Shibata, Masahiro, Takeuchi, Dai, Tsunoda, Nobuyuki, Kikumori, Toyone, Tanaka, Maki, Kodera, Yasuhiro, Kasuya, Hideki
• Format: Article
• Language: English
• Subjects: Original Paper
• ISSN: 0027-7622; 2186-3326
• DOI: 10.18999/nagjms.83.4.683

Canerpaturev (C-REV) is a highly attenuated, replication-competent, mutant strain of oncolytic herpes simplex virus type 1 that may be an effective new cancer treatment option. S-1, an oral formulation containing the 5-fluorouracil (5-FU) prodrug tegafur and the two enzyme modulators gimeracil and oteracil, is used as a key chemotherapeutic agent for metastatic recurrent breast cancer. Although the antitumor effects of oncolytic viruses combined with 5-FU in vivo have been reported, the detailed mechanisms are unknown. Here, we investigated the antitumor mechanism of the combination of C-REV and S-1 in triple-negative breast cancer (TNBC) in the context of tumor immunity. The combined effect of C-REV and S-1 was evaluated in a bilateral tumor model of murine TNBC 4T1 in vivo. S-1 enhanced the TNBC growth inhibitory effects of C-REV, and decreased the number of tumor-infiltrating, myeloid-derived suppressor cells (MDSCs), which suppress both innate and adaptive immune responses. Moreover, C-REV alone and in combination with S-1 significantly increased the number of CD8 + T cells in the tumor and the production of interferon γ (IFNγ) from these cells. Our findings indicate that C-REV suppresses TNBC tumor growth by inducing the expansion of effector CD8 + T cell subsets in tumors in which S-1 can inhibit MDSC function. Our study suggests that MDSCs may be an important cellular target for breast cancer treatment. The combination of C-REV and S-1 is a new approach that might be directly translated into future clinical trials against TNBC.