AMPK alpha-1 intrinsically regulates the function and differentiation of tumor myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSC) represent a primary mechanism of immune evasion in tumors and have emerged as a major obstacle for cancer immunotherapy. The immunoinhibitory activity of MDSC is tightly regulated by the tumor microenvironment (TME) and occurs through mechanistic mediators that remain unclear. Here, we elucidated the intrinsic interaction between the expression of AMP-activated protein kinase alpha (AMPK alpha) and the immunoregulatory activity of MDSC in tumors. AMPK alpha signaling was increased in tumor-MDSC from tumor-bearing mice and ovarian cancer patients. Transcription of the Ampk alpha-1-coding gene, Prkaa1, in tumor-MDSC was induced by cancer cell-derived granulocyte-monocyte colony-stimulating factor (GM-CSF) and occurred in a Stat-5-dependent manner. Conditional deletion of Prkaa1 in myeloid cells, or therapeutic inhibition of Ampk alpha in tumor-bearing mice, delayed tumor growth, inhibited the immunosuppressive potential of MDSC, triggered anti-tumor CD8+ T-cell immunity, and boosted the efficacy of T-cell immunotherapy. Complementarily, therapeutic stimulation of AMPK alpha signaling intrinsically promoted MDSC immunoregulatory activity. In addition, Prkaa1 deletion antagonized the differentiation of monocytic-MDSC (M-MDSC) to macrophages, and re-routed M-MDSC, but not granulocytic-MDSC (PMN-MDSC), into cells that elicited direct anti-tumor cytotoxic effects through nitric oxide synthase 2 (Nos2)-mediated actions. Thus, our results demonstrate the primary role of AMPK alpha-1 in the immunosuppressive effects induced by tumor-MDSC, and support the therapeutic use of AMPK-inhibitors to overcome MDSC-induced T-cell dysfunction in cancer.