Henrich, Frederik C. and Singer, Katrin and Poller, Kerstin and Bernhardt, Luise and Strobl, Carolin D. and Limm, Katharina and Ritter, Axel P. and Gottfried, Eva and Voelkl, Simon and Jacobs, Benedikt and Peter, Katrin and Mougiakakos, Dimitrios and Dettmer, Katja and Oefner, Peter J. and Bosserhoff, Anja-Katrin and Kreutz, Marina P. and Aigner, Michael and Mackensen, Andreas (2016) Suppressive effects of tumor cell-derived 5 '-deoxy-5 '-methylthioadenosine on human T cells. ONCOIMMUNOLOGY, 5 (8): e1184802. ISSN 2162-402X,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | METHYLTHIOADENOSINE PHOSPHORYLASE MTAP; PROTEIN ARGININE METHYLATION; 5'-METHYLTHIOADENOSINE PHOSPHORYLASE; S-ADENOSYLMETHIONINE; METASTATIC MELANOMA; PREDICTIVE MARKER; IMMUNE-RESPONSE; DOWN-REGULATION; INHIBITION; METABOLISM; Antitumor immune response; cell signaling; immunosuppression; MTA; MTAP; protein methylation; tumor metabolism; T cells |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 18 Mar 2019 11:06 |
| Last Modified: | 18 Mar 2019 11:06 |
| URI: | https://pred.uni-regensburg.de/id/eprint/2634 |
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