Mutant C/EBPα p30 alleviates immunosuppression of CD8 + T cells by inhibiting autophagy-associated secretion of IL-1β in AML.

Objectives: Mutant C/EBPα p30 (mp30), the product of C/EBPα double mutations (DM), lacks transactivation domain 1 and has C-terminal loss-of-function mutation. Acute myeloid leukaemia (AML) patients harbouring C/EBPα 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-κB. Autophagy-associated secretion of IL-1β was decreased in mp30-overexpressed AML cells. Bioinformatic analysis revealed that inflammatory status was attenuated, while CD8 ⁺ T cell infiltration was upregulated in C/EBPα 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-1β in AML cells also enhanced CD8 ⁺ T cell activation. Accordingly, IL-1β expression was significantly reduced in the bone marrow (BM) cells of C/EBPα DM AML patients compared to the wildtype, while the CD8 ⁺ CD69 ⁺ T cell proportion was specifically elevated.
Conclusions: C/EBPα DM alleviates immunosuppression of CD8 ⁺ T cells by inhibiting the autophagy-associated secretion of IL-1β, which elucidated that repression of autophagy-related inflammatory response in AML patients might achieve a favourable clinical benefit.
(© 2022 The Authors. Cell Proliferation published by European Cell Proliferation Society and John Wiley & Sons Ltd.)