The role of the immune system in the pathophysiology of acute myeloid leukemia

The immune system shapes the tumor microenvironment (TME), and a tight regulation of effector T cell responses is essential for effective immune surveillance and tumor suppression. In acute myeloid leukemia (AML), alterations of CD3+ T cells influence survival, relapse, and therapy resistance. Venetoclax (Ven)-based therapies, in particular its combination with hypomethylating agents (HMAs, decitabine or azacitidine) have improved outcomes in newly diagnosed unfit AML patients, yet relapse and refractoriness remain major challenges. These disease stages are associated with dysregulated polyamine metabolism, which also influences T cell proliferation, survival, and commitment. This project aims to investigate immune and genetic mechanisms underlying Ven-based therapies resistance in AML patients. Single-cell DNA/RNA sequencing showed that clonal evolution, transcriptional reprogramming and immune suppression mechanisms cooperate in patients relapsed/refractory to Ven combined with fludarabine, cytarabine, and idarubicin. Longitudinal single-cell RNA-seq of Ven/decitabine-treated patients (treatment-naïve, post-cycle 1, and relapse/refractory) revealed relapse-specific gene signatures both in the blast and T cell compartments. Network propagation identified key regulatory genes within blast, CD4+, and CD8+ T cell populations as potential therapeutic targets to be validated in AML cell lines intrinsically resistant to ven/decitabine or in which resistance has been induced in culture, followed by transcriptional profiling. In parallel, we have tested the consequences of drugs targeting polyamine metabolism on antileukemia T cell response, observing enhanced cytotoxicity when co-culturing CD3+ (but not CD8+) T cells with AML cell lines or autologous blasts, at least in a fraction of cases. Preliminary data suggests that regulatory T cells suppression ability may not be involved in the observed phenotype. Altogether, these results improve our understanding of T cell dysfunctions occurring under the pressure of Ven-based therapeutic regimens in AML and suggest novel therapeutic combinations aimed at both weakening leukemic cells and reinforcing the anti-leukemia immune response.