Harnessing Β-catenin and NK2GD to enable HLA-independent CD8+ T cell immunotherapy against AML - immunotherapy for acute myeloid leukemia (AML) is frequently limited by the downregulation of human…

The National Institutes of Health National Cancer Institute awarded The Research Foundation For The State University Of New York $724,196 on September 1, 2026, under the Cancer Biology Research program (CFDA 93.396) for a Project Grant (R01CA308325) investigating HLA-independent CD8+ T cell immunotherapy against acute myeloid leukemia.

The research develops a novel therapeutic strategy to overcome HLA Class I downregulation on leukemic cells, which enables tumors to evade conventional CD8+ T cell recognition. The funded work stabilizes β-catenin and selectively increases natural killer group 2 member D (NKG2D) expression on CD8+ T cells to enhance their cytotoxic capacity independent of HLA recognition. Preliminary findings demonstrate that A124, a small-molecule β-catenin activator, increases NKG2D expression and cytolytic activity in AML patient-derived CD8+ T cells without promoting exhaustion. Aim 1 delineates the molecular mechanisms of the β-catenin–T-BET–NKG2D regulatory axis in murine and human CD8+ T cells using genetic, molecular, and pharmacological approaches. Aim 2 evaluates translational potential by determining whether pharmacological β-catenin stabilization enhances antileukemic activity, preserves activating-receptor expression, limits T-cell exhaustion, and maintains genomic and systemic safety through advanced humanized mouse models engrafted with primary patient-derived AML cells and matched CD8+ T cells.

Performance occurs in Syracuse, New York. The project period extends from September 1, 2026, through August 31, 2031.

Harnessing Β-catenin and NK2GD to enable HLA-independent CD8+ T cell immunotherapy against AML - immunotherapy for acute myeloid leukemia (AML) is frequently limited by the downregulation of human leukocyte antigen class I (HLA-I) on leukemic cells, enabling tumors to evade recognition by conventional CD8. T cells. To overcome this critical barrier, we propose a novel therapeutic strategy that enhances the HLA-independent cytotoxic capacity of CD8. T cells by stabilizing Â-catenin and selectively increasing expression of the activating receptor natural killer group 2 member D (NKG2D). Our preliminary findings demonstrate that A124, a novel small-molecule Â-catenin activator, increases NKG2D expression and cytolytic activity in AML patient-derived CD8. T cells without promoting exhaustion. We hypothesize that Â-catenin stabilization through an AKT-mediated, WNT-independent pathway increases T-BET expression and activity, thereby directly activating the NKG2D promoter and reprogramming CD8. T cells toward a potent TCF-1-low effector phenotype. Aim 1 will define the molecular mechanisms governing this HLA-independent cytotoxic program. Using complementary genetic, molecular, and pharmacological approaches, we will delineate the Â-catenin-T-BET- NKG2D regulatory axis in murine and human CD8. T cells. Aim 2 will evaluate the translational potential of this pathway by determining whether pharmacological Â-catenin stabilization enhances antileukemic activity, preserves activating-receptor expression, limits T-cell exhaustion, and maintains genomic and systemic safety. Because these dynamic interactions cannot be fully modeled in vitro, advanced humanized mouse models engrafted with primary patient-derived AML cells and matched CD8. T cells are essential. These models provide a physiologically relevant tumor microenvironment in which to evaluate longitudinal antitumor activity, T-cell persistence and exhaustion, systemic toxicity, and the therapeutic efficacy of A124. Collectively, this research will uncover a previously unrecognized mechanism through which Â-catenin programs HLA-independent CD8. T-cell cytotoxicity. These studies will establish the preclinical foundation for developing Â-catenin-targeted immunotherapies capable of overcoming immune evasion in AML.