Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells

Abstract

The immunosuppressive tumor microenvironment represents one of the main obstacles for immunotherapy of cancer. The tumor milieu is among others shaped by tumor metabolites such as 5 0 -deoxy-5 0 -methylthioadenosine (MTA). Increased intratumoral MTA levels result from a lack of the MTAcatabolizing enzyme methylthioadenosine phosphorylase (MTAP) in tumor cells and are found in various tumor entities. Here, we demonstrate that MTA suppresses proliferation, activation, differentiation, and effector function of antigen-specific T cells without eliciting cell death. Conversely, if MTA is added to highly activated T cells, MTA exerts cytotoxic effects on T cells. We identified the Akt pathway, a critical signal pathway for T cell activation, as a target of MTA, while, for example, p38 remained unaffected. Next, we provide evidence that MTA exerts its immunosuppressive effects by interfering with protein methylation in T cells. To confirm the relevance of the suppressive effects of exogenously added MTA on human T cells, we used an MTAP-deficient tumor cell-line that was stably transfected with the MTAPcoding sequence. We observed that T cells stimulated with MTAP-transfected tumor cells revealed a higher proliferative capacity compared to T cells stimulated with Mock-transfected cells. In conclusion, our findings reveal a novel immune evasion strategy of human tumor cells that could be of interest for therapeutic targeting.

MTAP loss correlates with an immunosuppressive profile in GBM and its substrate MTA stimulates alternative macrophage polarization

“…It has previously been demonstrated that MTA can directly suppress the proliferation and function of T lymphocytes (24,67). Our findings complement these studies by showing that MTA, which accumulates in MTAP-deficient tumor cells, can also influence innate immune cells.…”

“…MTA is known to be functionally active within cells as an inhibitor of methyltransferases (22,23). This metabolite has also been shown to suppress cell proliferation via different, cellular context-dependent mechanisms, including targeting the Akt signal pathway and interfering with intracellular protein methylation in T cells (24), or acting through adenosine receptors on the cell surface of melanoma cell lines (25). Studies on mechanism of pathogen-induced host inflammatory responses have linked MTA to downregulation of TNFα production by macrophages through engaging adenosine receptors (26), and have revealed a role of MTA in controlling host inflammation response, such that MTA has been used as an immunosuppressive drug for treating colitis, liver inflammation, brain inflammation and autoimmunity in animal models (27)(28)(29).…”

PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis

“…It has been recently shown that alterations in the tumor environment result in high tumoral MTA levels that inhibit protein arginine methylation and suppress anti-cancer human T cell responses. Accumulating evidence therefore hints that the T cell effects of global methyltransferase inhibition are due to inhibition of Protein Arginine Methyl Transferases (PRMT) (29, 30). However, conclusive evidence demonstrating that PRMTs are responsible for T cell suppression, as well as a specific role for the main symmetric dimethylation enzyme PRMT5, has been lacking.…”

Understanding the Intersections between Metabolism and Cancer Biology

“…Kynurenine, a breakdown product of tryptophan, can modulate both the innate and adaptive immune system and has been implicated in cancer-associated immunosuppression (Platten et al, 2014) and indoleamine-2,3-dioxygenase (IDO) inhibitors that decrease tryptophan metabolism can help break immune tolerance and potentiate chemotherapy (Muller et al, 2005). Increased MTA levels in MTAP-null tumors can also suppress T cell activation (Henrich et al, 2016) and suggests some metabolic interventions might enhance anti-cancer immune responses.…”