Suppressive effects of tumor cell-derived 5'-deoxy-5'-methylthioadenosine on human T cells.
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.
Department of Internal Medicine 5 - Hematology and Oncology, University Hospital of Erlangen , Erlangen, Germany.
Frederik C
FC
Henrich
Department of Internal Medicine 5 - Hematology and Oncology, University Hospital of Erlangen, Erlangen, Germany; Department of Internal Medicine 3 - Hematology and Oncology, University Hospital of Regensburg, Regensburg, Germany.
Katrin
K
Singer
Department of Internal Medicine 5 - Hematology and Oncology, University Hospital of Erlangen , Erlangen, Germany.
Kerstin
K
Poller
Department of Internal Medicine 5 - Hematology and Oncology, University Hospital of Erlangen , Erlangen, Germany.
Luise
L
Bernhardt
Department of Internal Medicine 5 - Hematology and Oncology, University Hospital of Erlangen , Erlangen, Germany.
Carolin D
CD
Strobl
Institute of Biochemistry - Emil-Fischer-Zentrum, Friedrich-Alexander University of Erlangen-Nuremberg , Erlangen, Germany.
Katharina
K
Limm
Institute of Functional Genomics, University of Regensburg , Regensburg, Germany.
Axel P
AP
Ritter
Department of Internal Medicine 3 - Hematology and Oncology, University Hospital of Regensburg , Regensburg, Germany.
Eva
E
Gottfried
Department of Internal Medicine 5 - Hematology and Oncology, University Hospital of Erlangen , Erlangen, Germany.
Simon
S
Völkl
Department of Internal Medicine 5 - Hematology and Oncology, University Hospital of Erlangen, Erlangen, Germany; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Radiumhospital, Oslo, Norway; The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Benedikt
B
Jacobs
Department of Internal Medicine 3 - Hematology and Oncology, University Hospital of Regensburg , Regensburg, Germany.
Katrin
K
Peter
Department of Internal Medicine 5 - Hematology and Oncology, University Hospital of Erlangen , Erlangen, Germany.
Dimitrios
D
Mougiakakos
Institute of Functional Genomics, University of Regensburg , Regensburg, Germany.
Katja
K
Dettmer
Institute of Functional Genomics, University of Regensburg , Regensburg, Germany.
Peter J
PJ
Oefner
Institute of Biochemistry - Emil-Fischer-Zentrum, Friedrich-Alexander University of Erlangen-Nuremberg , Erlangen, Germany.
Anja-Katrin
AK
Bosserhoff
Department of Internal Medicine 3 - Hematology and Oncology, University Hospital of Regensburg , Regensburg, Germany.
Marina P
MP
Kreutz
Department of Internal Medicine 5 - Hematology and Oncology, University Hospital of Erlangen , Erlangen, Germany.
Michael
M
Aigner
Department of Internal Medicine 5 - Hematology and Oncology, University Hospital of Erlangen , Erlangen, Germany.
Andreas
A
Mackensen
Antitumor immune response; MTA; MTAP; T cells; cell signaling; immunosuppression; protein methylation; tumor metabolism