BioAxone BioSciences (United States)

Abstract We previously discovered that BM-derived Mesenchymal stromal cells (BM-MSCs) are migrating to the stroma of numerous cancers and their metastasis, forming TAFs and secrete proteins intra-tumorally. MSCs have not been used in cancer therapy because of their immune suppressive properties, limited replicative capacity, source dependent quality and controversial roles in cancer biology. Here, we report the characterization of novel MSCs (iMSCs), which were generated from adult skin fibroblast-derived induced pluripotent stem cells (iPSC). These iPSCs were generated via a unique, transient mRNA transfection technique and subsequently differentiated into iMSCs. Notably, iMSCs displayed contact inhibition and significantly enhanced proliferative capacity under both normoxic and hypoxic conditions, outperforming bone marrow-derived MSCs (BM-MSCs) while fully retaining trilineage differentiation potential. Comprehensive molecular profiling, including RNA sequencing, single-cell mass cytometry (CyTOF), and Luminex assays, revealed strong phenotypic and functional resemblance between iMSCs and BM-MSCs. Crucially, no sarcoma formation was detected in NSGS mice following intraperitoneal, subcutaneous, or intravenous administration of iMSCs, underscoring their safety profile. We further engineered a DNA cassette into these cells to enable IL-7 and IL-15 cytokine production, expressed as either individual molecules (P2A) or a single fused molecule (FUS). Both P2A and FUS cells demonstrated the capacity to drive T cell proliferation autonomously in co-culture. Cytokine secretion from these modified iMSCs enhanced tumor cell death in a triple co-culture system comprising iMSCs, the ovarian cancer cell line ID8, and human PBMCs. In a syngeneic mouse model of ovarian cancer (ID8 in C57BL/6 mice), administration of P2A or FUS MSCs resulted in reduced tumor growth and extended survival. Immunohistochemical and flow cytometric analyses revealed massive infiltration of T cells, macrophages, NK cells, and other immune cells into the tumor microenvironment (TME) in both FUS or P2A groups, but not in control, unmodified MSC, or PBS injected animals. Moreover, the TME in P2A- and FUS-treated mice showed enrichment in M1-type macrophages, with no detection of any of the T cell exhaustion markers tested, in contrast to the control groups (PBS or GFP-iMSC). In conclusion, our findings indicate that IL7-IL15-secreting iMSCs migrate into solid tumors, induce massive immune cell infiltration into the TME and enhance antitumor immunity in a syngeneic mouse model of cancer. These cytokine-producing iMSCs represent a promising therapeutic strategy for modulating the immune response against tumors and advancing anticancer immunotherapy by converting “cold” into “hot” tumor microenvironments. Citation Format: Sandeep Singh, Andrea Bedoy, Dipmoy Nath, Kyung Hee Chang, Lauren B. Ostermann, Ivo Veletic, Christopher D. Pacheco, Po Yee Mak, Edward Ayoub, Muharrem Muftuoglu, Mahesh Basyal, Taeyun Kim, Raven Dance Hinkel, Kyle M. Garland, Matthew Angel, Sanjeev Luther, Christopher B. Rohde, Michael Andreeff. iPS-derived MSC secreting IL7 and IL15 exert immune mediated anti-tumor activities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3473.

Aging is characterized by increased mortality, functional decline, and exponential increases in the incidence of diseases such as cancer, stroke, cardiovascular disease, neurological disease, respiratory disease, etc. Though the role of aging in these diseases is widely accepted and considered to be a common denominator, the underlying mechanisms are largely unknown. A significant age-related feature observed in many population cohorts is somatic mosaicism, the detectable accumulation of somatic mutations in multiple cell types and tissues, particularly those with high rates of cell turnover (e.g., skin, liver, and hematopoietic cells). Somatic mosaicism can lead to the development of cellular clones that expand with age in otherwise normal tissues. In the hematopoietic system, this phenomenon has generally been referred to as “clonal hematopoiesis of indeterminate potential” (CHIP) when it applies to a subset of clones in which mutations in driver genes of hematologic malignancies are found. Other mechanisms of clonal hematopoiesis, including large chromosomal alterations, can also give rise to clonal expansion in the absence of conventional CHIP driver gene mutations. Both types of clonal hematopoiesis (CH) have been observed in studies of animal models and humans in association with altered immune responses, increased mortality, and disease risk. Studies in murine models have found that some of these clonal events are involved in abnormal inflammatory and metabolic changes, altered DNA damage repair and epigenetic changes. Studies in long-lived individuals also show the accumulation of somatic mutations, yet at this advanced age, carriership of somatic mutations is no longer associated with an increased risk of mortality. While it remains to be elucidated what factors modify this genotype-phenotype association, i.e., compensatory germline genetics, cellular context of the mutations, protective effects to diseases at exceptional age, it points out that the exceptionally long-lived are key to understand the phenotypic consequences of CHIP mutations. Assessment of the clinical significance of somatic mutations occurring in blood cell types for age-related outcomes in human populations of varied life and health span, environmental exposures, and germline genetic risk factors will be valuable in the development of personalized strategies tailored to specific somatic mutations for healthy aging.

5-androstene-3β,7β,17β-triol (β-AET), an active metabolite of dehydroepiandrosterone (DHEA), reversed glucocorticoid (GC)-induced suppression of IL-6, IL-8 and osteoprotegerin production by human osteoblast-like MG-63 cells and promoted osteoblast differentiation of human mesenchymal stem cells (MSCs). In a murine thermal injury model that includes glucocorticoid-induced osteopenia, β-AET significantly (p<0.05) preserved bone mineral content, restored whole body bone mineral content and endochondral growth, suggesting reversal of GC-mediated decreases in chondrocyte proliferation, maturation and osteogenesis in the growth plate. In men and women, levels of β-AET decline with age, consistent with a role for β-AET relevant to diseases associated with aging. β-AET, related compounds or synthetic derivatives may be part of effective therapeutic strategies to accelerate tissue regeneration and prevent or treat diseases associated with aging such as osteoporosis.