Suppressive effects of tumor cell-derived 5'-deoxy-5'-methylthioadenosine on human T cells

Frederik C Henrich, Katrin Singer, Kerstin Poller, Luise Bernhardt, Carolin D Strobl, Katharina Limm, Axel P Ritter, Eva Gottfried, Simon Völkl, Benedikt Jacobs, Katrin Peter, Dimitrios Mougiakakos, Katja Dettmer, Peter J Oefner, Anja-Katrin Bosserhoff, Marina P Kreutz, Michael Aigner, Andreas Mackensen
Oncoimmunology 2016, 5 (8): e1184802
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'-deoxy-5'-methylthioadenosine (MTA). Increased intratumoral MTA levels result from a lack of the MTA-catabolizing 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 MTAP-coding 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.

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