Tumor-associated myeloid cells support T-ALL survival and proliferation through close contact

Abstract

Abstract T cell acute lymphoblastic leukemia (T-ALL) is a malignancy of developing T cells. Although intensified radiation and chemotherapy have improved survival rates to ~85% in pediatric patients, these therapies are toxic, and patients who relapse have no alternative treatments. Research on the genetic mutations driving T-ALL have been extensively characterized, but despite numerous tumor-promoting genomic alterations, primary T-ALL cells require cells/signals from the tumor microenvironment (TME) to survive. We have previously reported that myeloid cells from the TME are capable of supporting survival and proliferation of T-ALL cells in vitro. Here, we report that myeloid cells are required for T-ALL tumor growth in vivo. Treatment of a transplantable murine model of T-ALL with Clodronate liposomes, which deplete myeloid cells, resulted in a significant reduction in tumor burden in multiple tissues compared to control-treated mice. Because the myeloid compartment is heterogeneous, we assessed the capacity of purified myeloid subsets to support the survival of T-ALL cells, and identified several myeloid cell types capable of providing tumor support. To address the mechanism by which these tumor-associated myeloid cells support T-ALL growth, we performed transwell assays and found that T-ALL cells require close contact with myeloid cells to receive survival signals. We report on recent functional experiments, implicating VCAM-1 and ICAM-1 as important mediators of myeloid support of T-ALL. Future studies aim to provide further insight into the cell types and mechanisms by which stroma from the TME of distinct organs promote T-ALL survival, with the ultimate goal of developing effective therapeutics.