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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 stem-like T cells. In this study, we investigated multiple populations of CD8+ T cells, especially the stem-cell like T cells in T-ALL. We found low dose doxorubicin increased the naïve T cell and stem-like T cell pool. Moreover, our flow cytometry and single-cell sequencing analysis of LSCs and blast cells revealed upregulation of stem-like T cell gene signature after low DXR treatment, but not after conventional chemotherapy. Further functional analysis of the CD8 T cells reactive to leukemia is ongoing by in vitro culture. Meanwhile, we characterized T cells in patients with minimal residual disease (MRD). We found that MRD negative patients were presented with more naïve T cells, and enhanced polyfunctionality in their T 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-like T cells and preventing relapse in patients treated with immunotherapy.
Tao, Fang; McElroy, Sara; Nemechek, Jacqelyn; Pushel, Irina; Khanal, Santosh; Szarejko, John; Bradley, Todd; Myers, Douglas; and Perry, John M., "Stem Like T Cells in Anti-cancer Immunosurveillance Against Therapy-resistant Pediatric Cancer" (2023). Research at Children's Mercy Month 2023. 17.
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