Immune surveillance of acute myeloid leukemia is mediated by HLA-presented antigens on leukemia progenitor cells
Persistent therapy-resistant leukemia progenitor cells (LPC) are a main cause of disease relapse and recurrence in acute myeloid leukemia (AML). Specific LPC-targeting therapies may thus improve treatment outcome of AML patients. We demonstrated that LPCs present human leukocyte antigen (HLA)-restricted cancer antigens that induce T cell responses allowing for immune surveillance of AML. Using a mass spectrometry-based immunopeptidomics approach, we characterized the antigenic landscape of patient LPCs and identified AML/LPC-associated HLA-presented antigens including mutation-derived and cryptic neoepitopes as prime targets for development of T cell-based immunotherapeutic approaches. We observed frequent spontaneous memory T cells targeting these AML/LPC-associated antigens in AML patients and showed that antigen-specific T cell recognition and HLA class II immunopeptidome diversity impacts clinical outcome. Our results pave the way for implementation of AML/LPC-associated antigens for T cell-based immunotherapeutic approaches to specifically target and eliminate residual LPCs in AML patients. Overall design: In this study, we analyzed the expressional profile and T cell receptor (TCR) repertoire of antigen-specific CD4+ T cells from acute myeloid leukemia (AML) patients (n = 3). Therefore, PBMCs of AML patients were peptide-stimulated and sorted based on their IFN-g secretion. Single cell RNA sequencing (scRNA-seq) and single cell TCR profiling were performed using 10x Genomics single cell immune profiling.