The Role Of Stem Cell-Like Memory T Cells In Anti-Cancer Immunosurveillance Against Therapy-Resistant Pediatric Cancer

Authors

Fang Tao, Children's Mercy HospitalFollow
Sara McElroy, Children's Mercy Kansas CityFollow
John Szarejko, Children's Mercy Kansas CityFollow
Jacqelyn Nemechek, Children's Mercy HospitalFollow
Jennifer Pace, Children's Mercy HospitalFollow
Kealan Schroeder, Children's Mercy Kansas CityFollow
Santosh Khanal, Children's Mercy HospitalFollow
Todd Bradley, Children's Mercy HospitalFollow
Douglas Myers, Children's Mercy HospitalFollow
John M. Perry, Children's Mercy HospitalFollow

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Publication Date

5-2021

Abstract

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.

Document Type

Poster

Recommended Citation

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.
https://scholarlyexchange.childrensmercy.org/research_month2021/28