In Vitro Insights Into the Influence of Marrow Mesodermal/Mesenchymal Progenitor Cells on Acute Myelogenous Leukemia and Myelodysplastic Syndromes.

The study of marrow-resident mesodermal progenitors can provide important insight into their role in influencing normal and aberrant hematopoiesis as occurs in acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). In addition, the chemokine competency of these cells provides links to the inflammatory milieu of the marrow microenvironment with additional implications for normal and malignant hematopoiesis. While in vivo studies have elucidated the structure and function of the marrow niche in murine genetic models, corollary human studies have not been feasible, and thus the use of culture-adapted mesodermal cells has provided insights into the role these rare endogenous niche cells play in physiologic, malignant, and inflammatory states. This review focuses on culture-adapted human mesenchymal stem/stromal cells (MSCs) as they have been utilized in understanding their influence in AML and MDS as well as on their chemokine-mediated responses to myeloid malignancies, injury, and inflammation. Such studies have intrinsic limitations but have provided mechanistic insights and clues regarding novel druggable targets.

GM-CSF and IL-7 fusion cytokine engineered tumor vaccine generates long-term Th-17 memory cells and increases overall survival in aged syngeneic mouse models of glioblastoma.

Age-related immune dysfunctions, such as decreased T-cell output, are closely related to pathologies like cancers and lack of vaccine efficacy among the elderly. Engineered fusokine, GIFT-7, a fusion of interleukin 7 (IL-7) and GM-CSF, can reverse aging-related lymphoid organ atrophy. We generated a GIFT-7 fusokine tumor vaccine and employed it in aged syngeneic mouse models of glioblastoma and found that peripheral vaccination with GIFT-7TVax resulted in thymic regeneration and generated durable long-term antitumor immunity specifically in aged mice. Global cytokine analysis showed increased pro-inflammatory cytokines including IL-1ß in the vaccinated group that resulted in hyperactivation of dendritic cells. In addition, GIFT-7 vaccination resulted in increased T-cell trafficking to the brain and robust Th-17 long-term effector memory T-cell formation. TCR-seq analysis showed increased productive frequency among detected rearrangements within the vaccinated group. Overall, our data demonstrate that aging immune system can be therapeutically augmented to generate lasting antitumor immunity.