Mutant C/EBP alpha p30 alleviates immunosuppression of CD8(+) T cells by inhibiting autophagy-associated secretion of IL-1 beta in AML

Objectives Mutant C/EBP alpha p30 (mp30), the product of C/EBP alpha double mutations (DM), lacks transactivation domain 1 and has C-terminal loss-of-function mutation. Acute myeloid leukaemia (AML) patients harbouring C/EBP alpha DM could be classified as a distinct subgroup with favourable prognosis. However, the underlying mechanism remains elusive. Materials and Methods Autophagy regulated by mp30 was detected by western blot and immunofluorescence. Immune infiltration analysis and GSEA were performed to investigate autophagic and inflammatory status of AML patients from the GSE14468 cohort. Flow cytometry was applied to analyse T cell activation. Results Mp30 inhibited autophagy by suppressing nucleus translocation of NF-kappa B. Autophagy-associated secretion of IL-1 beta was decreased in mp30-overexpressed AML cells. Bioinformatic analysis revealed that inflammatory status was attenuated, while CD8(+) T cell infiltration was upregulated in C/EBP alpha DM AML patients. Consistently, the proportion of CD8(+)CD69(+) T cells in peripheral blood mononuclear cells (PBMCs) was upregulated after co-culture with mp30 AML cell conditional culture medium. Knock-out of IL-1 beta in AML cells also enhanced CD8(+) T cell activation. Accordingly, IL-1 beta expression was significantly reduced in the bone marrow (BM) cells of C/EBP alpha DM AML patients compared to the wildtype, while the CD8(+)CD69(+) T cell proportion was specifically elevated. Conclusions C/EBP alpha DM alleviates immunosuppression of CD8(+) T cells by inhibiting the autophagy-associated secretion of IL-1 beta, which elucidated that repression of autophagy-related inflammatory response in AML patients might achieve a favourable clinical benefit.