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

Henrich F, Singer K, Poller K, Bernhardt L, Strobl C, Limm K, Ritter AP, Gottfried E, Voelkl S, Jacobs B, Peter K, Mougiakakos D, Dettmer K, Oefner PJ, Boßerhoff AK, Kreutz MP, Aigner M, Mackensen A (2016)

Publication Type: Journal article

Publication year: 2016

Journal

OncoImmunology Taylor & Francis

Book Volume: 5

Pages Range: e1184802

Journal Issue: 8

DOI: 10.1080/2162402X.2016.1184802

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.

Authors with CRIS profile

Frederik Henrich Professur für Mikrobiologie Carolin Strobl Department of Medicine 5 – Haematology and Oncology Katharina Limm Lehrstuhl für Biochemie und Molekulare Medizin Anja Katrin Boßerhoff Lehrstuhl für Biochemie und Molekulare Medizin Andreas Mackensen Lehrstuhl für Innere Medizin V

Involved external institutions

Universität Regensburg DE Germany (DE) Universitätsklinikum Regensburg DE Germany (DE)

How to cite

APA:

Henrich, F., Singer, K., Poller, K., Bernhardt, L., Strobl, C., Limm, K.,... Mackensen, A. (2016). Suppressive effects of tumor cell-derived 5'-deoxy-5'-methylthioadenosine on human T cells. OncoImmunology, 5(8), e1184802. https://dx.doi.org/10.1080/2162402X.2016.1184802

MLA:

Henrich, Frederik, et al. "Suppressive effects of tumor cell-derived 5'-deoxy-5'-methylthioadenosine on human T cells." OncoImmunology 5.8 (2016): e1184802.

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