Download Full Text (2.4 MB)
Leukemia is the most commonly diagnosed pediatric cancer. Acute lymphoblastic leukemia (ALL) has an 85% 5-year-survival rate; yet 20% of patients experience relapse driven by therapy-resistant cells and do not survive long-term. The Wnt/β-catenin and PI3K/Akt signalling pathways interact to confer resistance to cancer therapies. We previously found low dose doxorubicin (DXR) specifically target therapy-resistant leukemic stem cells (LSCs) by inhibiting immune check point genes on LSCs in a T-cell acute lymphoblastic leukemia (T-ALL) mouse model. However, the cellular and molecular mechanisms of how low DXR functions to achieve this anti-cancer immunity are not well understood. Wnt signaling was shown to arrest effector cell differentiation and generate memory stem cells, which preserves anti-tumor potential. As DXR inhibits the cooperative interaction of Akt and β-catenin, we hypothesized that low DXR facilitates immune reactivation against resistant LSCs by regulating T memory stem cells. In this study, we investigated the role of stem-cell like memory T cells in T-ALL. We found that the bone marrow and spleen of T-ALL mice showed exhausted naïve CD8 T cells. Intriguingly, these cells expressed higher levels of surface proteins with stem-like features. Low dose doxorubicin restored the naïve T cell pool, but paradoxically reduced the stem cell-like memory T cells. Further functional analysis of the reactive T memory stem cells by in vitro culture and allogeneic transplantation is ongoing. Furthermore, our single-cell sequencing analysis of flow cytometry sorted LSCs and blast cells revealed significant transcriptome changes after low DXR treatment, further illuminating the nature of T memory stem cells. Meanwhile, we are characterizing the human counterpart of T memory stem cells. These cells may ultimately be pharmacologically stimulated by low DXR while genetically engineered to express chimeric antigen receptors, allowing application of adoptive immunotherapy based on the tumor-specific stem memory T cells and preventing relapse in patients treated with immunotherapy.
Tao, Fang; McElroy, Sara; Szarejko, John; Nemechek, Jacqelyn; Pace, Jennifer; Schroeder, Kealan; Khanal, Santosh; Bradley, Todd; Myers, Douglas; and Perry, John M., "The Role Of Stem Cell-Like Memory T Cells In Anti-Cancer Immunosurveillance Against Therapy-Resistant Pediatric Cancer" (2021). Research at Children's Mercy Month 2021. 28.