Abstract
Tumor cells develop various mechanisms to escape immune surveillance. In this context, oncometabolites secreted by tumor cells due to deregulated metabolic pathways, have been in the spotlight of researchers during the last years. 5′-Deoxy-5′-methylthioadenosine (MTA) phosphorylase (MTAP) deficiency in tumors results in the accumulation of MTA within the tumor microenvironment and thereby negatively influencing immune functions of various immune cells, including T and NK cells. The influence of MTA on T cell activation has been recently described in more detail, while its impact on NK cells is still largely unknown. Therefore, we aimed to illuminate the molecular mechanism of MTA-induced NK cell dysfunction. NK cell cytotoxicity against target cells was reduced in the presence of MTA in a dose-dependent manner, while NK cell viability remained unaffected. Furthermore, we revealed that MTA blocks NK cell degranulation and cytokine production upon target cell engagement as well as upon antibody stimulation. Interestingly, the immune-suppressive effect of MTA was less pronounced in healthy donors harboring an expansion of NKG2C+ NK cells. Finally, we demonstrated that MTA interferes with various signaling pathways downstream of the CD16 receptor upon NK cell activation, including the PI3K/AKT/S6, MAPK/ERK, and NF-κB pathways. In summary, we revealed that MTA blocks NK cell functions like cytotoxicity and cytokine production by interfering with the signaling cascade of activating NK cell receptors. Specific targeting of MTA metabolism in MTAP-deficient tumors therefore could offer a promising new strategy to reverse immune dysfunction of NK cells within the tumor microenvironment.
Highlights
Altered tumor cell metabolism is able to contribute to various tumor escape mechanisms to evade destruction by the immune system
Antibodies were purchased for CD16 biotin from BioLegend; LFA-1 open conformation isoform was from Abcam; pZAP/Syk, pS6, pSLP76, pAKT (S473), pPLCγ2, pERK1/2, and NF-κB pp65 were from BD; KIR2DL1/S1 was from Miltenyi; KIR2DL2/3/S2 was from Beckman Coulter; KIR3DL1/2 was from BioLegend; CD57 was from BioLegend; NKG2A was from Beckman Coulter; NKG2C was from Miltenyi; CD56 was from Beckman Coulter; CD16 was from BioLegend; 7AAD was from BD; dead-cell marker was from Life Technologies; and CD107a was from BioLegend
Since NK cells are known for their cytotoxic activity against various tumor cell lines, we were interested if MTA is capable of suppressing this effect
Summary
Altered tumor cell metabolism is able to contribute to various tumor escape mechanisms to evade destruction by the immune system. Various tumor entities have shown a reduced activity of the 5′-deoxy5′-methylthioadenosine phosphorylase (MTAP), an important enzyme of the polyamine and methionine salvage pathway, either due to promoter hypermethylation or deletion of the chromosomal 9p21 region [3,4,5]. MTAP is the only human enzyme that converts 5′-deoxy-5′-methylthioadenosine (MTA), a by-product of the polyamine pathway, into adenine and 5′methylthioribose-1-phosphate. The latter one is further metabolized to methionine within the methionine salvage pathway, which assures a sufficient production of S-adenosylmethionine (SAM/AdoMet), the most important methyl donor within eukaryotic cells. An immunesuppressive effect of MTA has been demonstrated as well within cells of the innate immune system including macrophages [9, 10] and NK cells [11]
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