Associations between recurrent mutations and blast immunophenotype in acute myeloid leukemia

Abstract

The immune system undoubtly plays an important role in final elimination of residual leukemic cells during acute myeloid leukemia (AML) therapy. However, the anti-leukemia immune response can be inhibited by a variety of mechanisms enabling immune escape and eventual disease relapse. We analyzed selected markers of immune escape on AML cells at diagnosis (N = 53) and used them for hierarchical clustering analysis, which yielded distinct clusters with different incidence of mutations in nucleophosmin 1 (NPM1) and in the methyltransferase DNMT3A. More detailed analysis showed that in the absence of DNMT3A mutation, NPM1 mutation is associated with decreased HLA expression and also with low levels of other markers (CLIP, PD-L1, TIM-3). On the other hand, samples with concomitant DNMT3A mutation had high CLIP surface amount suggesting reduced antigen presentation. Higher CLIP exposition was also found in patients with internal tandem duplications in FLT3 (FLT3-ITD). TIM-3 transcript correlated not only with TIM-3 protein surface amount, but also with CLIP and PD-L1, suggesting acquisition of a complex immunoresistant phenotype. Our results indicate that AML genotype is to some extent related to the blast immunophenotype, and the established predictive values of particular mutations might also reflect an inherent cell resistance to the immune system.

The correlation between Flt3-ITD mutation in dendritic cells with TIM-3 expression in acute myeloid leukemia

“…Leukemia cells can escape elimination by cytotoxic T-cells when they express lower levels of HLA class I. 20 We previously mentioned CLIP is an invariant chain peptide that is needed for antigen presentation with HLA class II in the exogenous pathway. The CLIP protein can also be cross-presented on HLA class I.…”

“…Flt3-ITD was associated with higher positivity of CD4+ T-cells for TIM-3. 20 Therefore, TIM-3 expression on dendritic cells is also possibly related to the Flt3-ITD mutation on DCs. However, there is a need for future research in this field and prove this correlation.…”

“… 20 , 23 We only partially understand how it functions in leukemia cells and it is likely complicated. 20 In the bone marrow and peripheral blood of AML patients, exhausted T cells have different phenotypes between subsets. 23 Li et al have reported that CD4 ∗ and CD8 ∗ T cells from recently diagnosed AML patients express more TIM-3 than those from normal controls.…”

“…The TIM-3 transcript appears to be correlated with CLIP expression, this suggests that immune escape mechanisms are frequently activated simultaneously. 20 Additionally, Flt3-ITD is linked to a higher positivity of CD4 ∗ T cells for TIM-3, an immunosuppressive molecule. 22 , 23 Kuželová et al showed that high levels of TIM-3 and CLIP are correlated with worse prognosis.…”

“…Immune evasion involves decreasing HLA expression, which impairs CD4 ∗ or CD8 ∗ T-cell recognition of antigen-specific tumors. Leukemia cells can escape elimination by cytotoxic T-cells when they express lower levels of HLA class I 20 . We previously mentioned CLIP is an invariant chain peptide that is needed for antigen presentation with HLA class II in the exogenous pathway.…”