Abstract
Immune checkpoint pathways active in Acute Myeloid Leukemia (AML) patients, especially during the course of remission induction chemotherapy, have not been well studied. Although dominant in mediating T cell dysfunction in cancer, it is now well-accepted that interruption of PD-1/PD-L1 axes alone does not always completely restore T cell function, indicating the involvement of additional negative regulatory pathways, such as TIM-3/Gal-9, in promoting T cell exhaustion.Here, we characterized these pathways in AML patients enrolled in a phase I dose escalation trial that combined Selinexor, a Selective Inhibitor of Nuclear Export (SINE), with high-dose cytarabine (HiDAC) and mitoxantrone (Mito) (NCT02573363) as induction therapy.To monitor changes in expression of immune checkpoint receptors, multi-parameter flow cytometry was performed on peripheral blood and bone marrow biopsy specimens at diagnosis and following induction therapy in 26 AML patients. Expression of CD47, PD-L1, PD-L2 and Gal9 was assessed on CD34+ AML blasts, as well as on CD34− cell populations. In parallel, we evaluated expression of inhibitory (PD1, CTLA4, LAG3, TIM-3) and stimulatory (CD28, ICOS, CD137, OX40, CD40L, HLA-DR) co-receptors on CD4+ and CD8+ T cell subsets.Compared to baseline, the frequency of Gal9+ CD34− cells was significantly higher in patients with treatment failure (TF) than in those in complete remission (CR), and this finding correlated with increased TIM-3 expression on marrow-resident T cells in TF patients. Moreover, when we measured the expression level of PD-1 and TIM-3 in bone marrow samples compared to peripheral blood, TIM-3 was significantly higher in BM specimens.Our results suggest that targeting the Gal9/Tim-3 axis could be effective in combination with induction chemotherapy to increase the likelihood of complete remission in AML patients.
Highlights
Acute Myeloid Leukemia (AML) is characterized by a poor prognosis, even in patients who achieve a complete remission to initial therapy
Pvalues
Specimens from patients with high-risk AML enrolled in a prospective clinical trial that combined Selinexor with High-Dose Cytarabine (HiDAC)+Mito (NCT02573363) were employed to address the question of the incorporating checkpoint blockade in combination with chemotherapy as a means of immune-mediated protection, even for those patients that achieve remission
Summary
Acute Myeloid Leukemia (AML) is characterized by a poor prognosis, even in patients who achieve a complete remission to initial therapy. Leukemia cells exploit a variety of mechanisms to evade T-cell-mediated immunity, leading to disease progression and relapse [1,2,3,4]. PD-1/PD-L1 interactions are associated with immune evasion in pre-clinical leukemia models, as we and others have previously demonstrated [5, 6]. It was reported that overexpression of PD-1 on stroma/non-blast compartment and its ligands (PD-L1 and PD-L2) on CD34+ leukemia cells is associated with more aggressive leukemia and progression from Myelodysplastic syndromes (MDS) to AML or AML relapse [7, 8]. Clinical studies of PD-1 blockade are currently ongoing in patients with AML and MDS [9]
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