Immunotherapy with 4-1BBL-expressing iPSC-derived proliferating myeloid cells amplifies antigen-specific T cell infiltration in advanced melanoma

Among advanced melanomas, approximately 60% of the patients present with immunologic ignorance or intrinsic induction tumors need other therapeutic approaches to change an immunologically “cold tumor” to “hot tumor” by attracting T cells into tumors. We have established an immune cell therapy with immortalized induced pluripotent stem–cell (iPSC)–derived proliferating myeloid cells (iPSC–pMCs). The benefits of using iPSC−pMCs are the infinite proliferative capacity and ease of genetic modification. In this study, we introduced 4-1BBL gene to iPSC–pMCs with a genetic background of C57BL6 (iPSC–pMCs–41BBL). Cytokine array analysis was performed using supernatants of the spleen cells that were cocultured withiPSC–pMCs or iPSC–pMCs–41BBL. Multiple cytokines that are beneficial to cancer immunotherapy were upregulated. Peritoneal injections of iPSC–pMCs–41BBL inhibited tumor growth of peritoneally disseminated mouse melanoma and prolonged survival of mice than that of iPSC–pMCs. Furthermore, the numbers of antigen-specific CXCR6+CD8 T cells were significantly increased in the spleen and tumor tissues treated with epitope peptide-pulsed iPSC–pMCs–41BBL. These results suggest that iPSC−pMCs−41BBL could activate antigen–specific T cells and promote their infiltration into the tumor tissues. In future clinical applications, we plan to use human allogenic iPSC–pMCs to treat patients. We examined the anticancer effects of embryonic stem (ES) cell-derived pMC established from the 129Sv mouse strain, which has a different MHC class II compared to C57BL6 mouse. Allogenic ES–pMC could show anticancer effects and suggested that 4-1BBL-targeted therapeutic strategies also work in allogenic environments.