Molecular regulation of CD8 T cell exhaustion in a mouse model of acute lymphocytic leukemia

Abstract

Abstract Acute lymphocytic leukemia (ALL) is a rapidly progressive form of leukemia more commonly found in children. Individuals nonresponsive to or ineligible for traditional chemotherapy and allogeneic hematopoietic cell transplant turn to alternatives like immunotherapies. While promising, current FDA approved immunotherapies for ALL have varying efficacy rates. CD8 T cell dysfunction or exhaustion is a key contributor to immunotherapy resistance, yet the molecular mechanisms controlling CD8 T cell exhaustion in ALL remain unclear. Here we sought to define those mechanisms in a mouse model of ALL. We utilized a syngeneic B cell acute lymphocytic leukemia mouse model (B-ALL: Arf −/−p185 +BCR-ABL +pro-B cells) to profile the distribution and molecular features of B-ALL specific CD8 T cells across multiple tissue sites and disease stages. We also compared tumor-specific CD8 T cell responses across B-ALL and solid tumor models to define both conserved and B-ALL specific phenotypes. Our findings indicate that B-ALL specific CD8 T cells share conserved features of exhausted CD8s, but also exhibit exhaustion-features unique to B-ALL. Ongoing experiments seek to define the transcriptional and epigenetic mechanisms guiding B-ALL specific CD8 T cell exhaustion, which may facilitate adoptive cell therapy strategies to improve CD8 T cell function and immunotherapy efficacy. Supported by a grant from NIH (T32 GM133364)