Tumor-Treating Fields Induce RAW264.7 Macrophage Activation Via NK-?B/MAPK Signaling Pathways

Park, Jeong-In; Song, Kyung-Hee; Jung, Seung-Youn; Ahn, Jiyeon; Hwang, Sang-Gu; Kim, Joon; Kim, Eun Ho; Song, Jie-Young

Tumor-treating fields have recently been reported as a promising and noninvasive therapeutic approach for cancer therapy with good clinical results. The underlying mechanical mechanisms include the disruption of mitosis and selective killing of rapidly proliferating cells by delivering continuous (>18 h/d) low-intensity, intermediate-frequency, alternating electric fields to the tumor site. Tumor-treating fields ultimately lead to caspase-dependent or caspase-independent-induced apoptosis. [18] [19] [20] Tumor-treating fields have been shown to apply its antimitotic effects in preclinical systems of various cancers, including GBM through the similar molecular mechanisms of activity. 5, 6, 21, 22 Furthermore, TTFs have been tried in preclinical systems combined with cytotoxic, chemotherapeutic agents in order to enhance the general antitumor effects. Combined treatment of TTFs with these chemotherapeutic agents (microtubule inhibitors, nucleoside analogues, folate antimetabolites, alkylating agents, and immune checkpoint inhibitors) demonstrated an additive cytotoxic effect. Taxanes and TTFs showed a synergistic effect against cancer cells. 23 In addition, in in vitro preclinical models, TTFs were shown to expose calreticulin to the cell surface, which ultimately significantly decreased the tumor volume in vitro and to considerably decrease the tumor volume in combination with antiprogrammed T-cell death 1 to significantly increase antigenpresenting cell infiltration of the tumor. 24 These events show the potentiation of immunogenic cell death by the treatment of TTFs, 25 which needs further investigation. Although a large number of studies using TTFs as an anticancer therapy are ongoing, the influence of TTFs on normal tissues in the tumor microenvironment remains largely unknown. Thus, in the current study, we demonstrated that TTFs exert potential immunostimulatory activity via regulation of NF-kB/MAPK signaling pathways in RAW 264.7 macrophages.