Postdoctoral Researcher St. Jude Children's Research Hospital Memphis, Tennessee, United States
Introduction/Rationale: Given that myeloid malignancies remain resistant to T cell-based strategies, we sought to investigate whether factors in the tumor microenvironment contribute to T cell dysfunction that impedes therapeutic success.
Methods: To better understand the immunosuppressive factors in the myeloid microenvironment, we leveraged St. Jude's comprehensive multi-omic datasets to identify S100A9 as among the most elevated inflammatory transcripts in AML blasts. Examination of AML patient-derived plasma from diagnosis confirmed the elevation of S100A9 and prompted further investigation into the role of S100A9 in mediating T cell dysfunction. We performed phenotypic analyses and genome-wide DNA methylation profiling of T cells isolated from pediatric AML patients to compare the epigenetic programs to our established exhaustion signature.
Results: Functional and transcriptional analyses reveal that both S100A9 protein and AML plasma induce healthy donor-derived T cell dysfunction in vitro, as demonstrated by a phenotypic shift of naïve T cells towards TemRA, reduced cytotoxicity, and decreased proliferation in response to TCR stimulation. Furthermore, S100A9 significantly impacted T cell metabolism, with notable changes in mitochondrial membrane potential and increased total cellular ROS. Epigenetic profiling revealed reduced stemness of AML versus ALL patient-derived T cells. Specifically, AML patient-derived T cells displayed increased methylation of genes related to naivety, cytotoxicity, and TLR activation, as well as decreased methylation in genes associated with T cell differentiation, mitochondrial function, and cellular metabolism.
Conclusion: These findings indicate that S100A9 in the myeloid tumor microenvironment contributes to T cell dysfunction, which may limit the efficacy of T cell-based immunotherapies in pediatric AML.
