Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells. (2nd August 2016)

• Record Type: Journal Article
• Authors: Henrich, Frederik C.; Singer, Katrin; Poller, Kerstin; Bernhardt, Luise; Strobl, Carolin D.; Limm, Katharina; Ritter, Axel P.; Gottfried, Eva; Völkl, Simon; Jacobs, Benedikt; Peter, Katrin; Mougiakakos, Dimitrios; Dettmer, Katja; Oefner, Peter J.; Bosserhoff, Anja-Katrin; Kreutz, Marina P.; Aigner, Michael; Mackensen, Andreas
• Is Part Of: Oncoimmunology. Volume 5:Number 8(2016)
• Publication Date: 2016-08-02
• Subjects: Antitumor immune response -- cell signaling -- immunosuppression -- MTA -- MTAP -- protein methylation -- tumor metabolism -- T cells; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2016.1184802
• Languages: English
• ISSNs: 2162-402X

Abstract

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′-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.