Engineered IL7/IL15 secreting iPSC-derived mesenchymal stromal cells convert the immunosuppressive into immune-activated tumor microenvironments (TME) and potentiate antitumor immunity

Mesenchymal stromal cells (MSCs) derived from bone marrow (BM-MSCs) exhibit inherent tumor-tropic behavior (Andreeff M., Cancer Res. 2002, JNCI 2004). However, their finite proliferative lifespan, donor-to-donor variability, and senescence-associated transcriptional drift present barriers to clinical scalability. To address these limitations, we reprogrammed adult dermal fibroblasts into induced pluripotent stem cells (iPSCs) using a synthetic, non-integrating mRNA transfection system. These iPSCs were stably modified to express interleukin-7 and interleukin-15, prior to mesodermal lineage specification into MSCs (hereafter referred to as IL7-IL15-iMSCs). Flow cytometry and transcriptomic profiling confirmed expression of canonical MSC markers (CD73⁺CD90⁺CD105⁺), absence of hematopoietic or endothelial lineage antigens and trilineage differentiation potential. IL7-IL15-iMSCs secreted supraphysiologic levels of cytokines, converting immune-suppressive MSCs into immune-activating MSCs. In vitro, IL7-IL15-iMSCs induced potent T cell proliferation sustaining the long-term expansion of T cells, macrophages and CAR T cells in vitro, and induced tumor cell death in a triple co-culture system comprising IL7-IL15-iMSCs, the ovarian cancer cell line ID8, and human PBMCs. In a syngeneic mouse model of ovarian cancer (ID8 and platinum-resistant ID8 cells in C57BL/6 mice), intraperitoneal administration of IL7-IL15-MSCs resulted in reduced tumor burden and extended survival. Immunohistochemical and CyTOF analyses revealed massive infiltration of activated T cells, macrophages, and other immune cells into the tumor microenvironment (TME) as well as enrichment in tumoricidal M1-type macrophages, with no detection of exhausted or regulatory T cells, in contrast to controls. To mitigate pulmonary first-pass entrapment associated with systemic, intra-venous (IV) MSC delivery, we optimized a fractionated low-dose IV administration regimen in the orthotopic 4T1 triple-negative breast cancer model. Six weeks post IL7-IL15-iMSC IV administration, tissue IHC staining showed robust iMSC localization to the TME, infiltration of immune cells and tumor reduction as observed in ovarian cancer. Conclusion: These data establish IL7-IL15-iMSCs as a novel, immunologically active stromal cell platform capable of remodeling the TME and amplifying both innate and adaptive anti-tumor responses. IL7-IL15 iMSC convert an immune-suppressed into an immune-activated TME in diverse tumor types. The scalability of iPSC-derived MSCs, combined with synthetic mRNA reprogramming and stable cytokine expression, supports the suitability of this platform for clinical translation. A first clinical trial in ovarian cancer is under development.