Immunophenotype profiling classifies AML patient susceptibility to immunotherapies

Immunosuppression has been identified as a contributing factor to therapy resistance and recurrence in acute myeloid leukemia (AML). Despite the upregulation of immune checkpoints (ICs) in AML patients, clinical trials assessing IC inhibitors (ICIs) have produced inconsistent results, impeding further clinical adoption. This variability suggests a deficiency in methodologies for identifying AML patients who may benefit from ICI therapy. We propose that distinct AML subtypes follow unique pathways leading to T-cell dysfunction. By conducting immune profiling specific to AML blasts, we aim to identify subgroups with distinct immunological characteristics. Through an integrative omics approach and T-cell activation assays in AML co-cultures, combined with multiparametric FACS analysis to monitor T-cell functionality, we have observed three immunophenotypes.
A subgroup characterized by T-cell infiltration within the tumor microenvironment (TME), T-cell dysfunction, low major histocompatibility complex (MHC) expression, and high programmed death-ligand 1 (PD-L1) expression. This subgroup correlates with megakaryoblastic/erythroleukemic differentiation, a history of myelodysplastic syndrome, and early inhibited T-cell activation/proliferation signaling. A profile associated with myelomonocytic/monocytic AML differentiation, featuring a T-cell-depleted TME, enrichment of M2 macrophages, upregulated expression of MHC subunits, and elevated levels of immunosuppressive factors (V-domain Ig suppressor of T-cell activation [VISTA], galectins, and T-cell immunoglobulin and mucin domain-containing protein 3 [TIM-3]). An immunostimulatory subgroup characterized by low MHC and immune marker gene expression levels.
Our findings highlight distinct AML immunophenotypes linked to diverse immunomodulatory factors, maturation stages, and their modulatory effects on T-cell activation and proliferation. These subtypes hold promise for predicting responders to potential combination therapies, including immunotherapies.