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.