AML induces TTCR-C4 NK-like transcriptional skewing associated with low persistence and dysfunction
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE285214 | GEO | 2025/04/16
REPOSITORIES: GEO
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Project description:Acute myeloid leukemia (AML) relapse is associated with a poor prognosis. Natural killer (NK) cells therapy induce leukemia remission; however, NK cells were susceptible to be exhausted post infusion. Determination of the mechanism of NK cell exhaustion in AML patients may provide insights for enhancing AML therapy. Here, we investigated NK cell exhaustion in relapsed AML patients post allo-HSCT based on phenotypic, functional, and RNA sequencing analyses. Compared with those from the complete remission and healthy control groups, NK cells from the relapsed group exhibited less maturity, higher inhibitory receptor expression and poorer cytotoxicity. AML cells could induce NK cell exhaustion through inhibition of PI3K-AKT pathway. Activation of PI3K-AKT was effective to increase NK cell cytotoxicity in exhausted NK cells. Excessive activation of the NKG2A/HLA-E axis is responsible for the inhibition of the PI3K-AKT pathway. Anti-HLA-E restored NK cell cytotoxicity against AML by increasing the phosphorylation of AKT in exhausted NK cells and knockout of the klrc1 in NK92 cells increased the phosphorylation of AKT and cytotoxicity against THP-1 cells. Moreover, blocking NKG2A was effective in controlling NK cell exhaustion and promoting cytotoxicity in AML mice. In summary, AML cells induced NK cell exhaustion via excessive activation of NKG2A/HLA-E axis and inhibition on PI3K-AKT pathway. Blocking the NKG2A axis is an effective way to reverse the inhibition of PI3K-AKT signaling on exhausted NK cells.
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Project description:HLA-E molecules can present self and pathogen-derived peptides to both NK-cells and T-cells. T-cells that recognize HLA-E peptides via their T-cell receptor (TCR) are termed donor-unrestricted T-cells due to restricted allelic variation of HLA-E. The composition and repertoire of HLA-E TCRs is not known so far. We performed TCR sequencing on CD8+ T-cells from 21 individuals recognizing HLA-E tetramers (TM) folded with 2 Mtb HLA-E restricted peptides. We sorted HLA-E Mtb TM+ and TMCD8+ T-cells directly ex vivo and performed bulk RNA-sequencing and single cell TCR sequencing. The identified TCR repertoire was diverse and showed no conservation between and within individuals. TCRs selected from our single cell TCR sequencing data could be activated upon HLA-E/peptide stimulation, although not robust, reflecting potentially weak interactions between HLA-E peptide complexes and TCRs. Thus, HLA-E Mtb specific T-cells have a highly diverse TCR repertoire.
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