Selective PRMT5 Inhibitors Suppress Human CD8+ T Cells by Upregulation of p53 and Impairment of the AKT Pathway Similar to the Tumor Metabolite MTA

Strobl C, Schaffer S, Haug T, Peter K, Singer K, Böttcher M, Mougiakakos D, Mackensen A, Aigner M, Völkl S (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Molecular Cancer Therapeutics American Association for Cancer Research

Book Volume: 19

Pages Range: 409-419

Journal Issue: 2

DOI: 10.1158/1535-7163.MCT-19-0189

Abstract

Genetic alterations in tumor cells provide promising targets for antitumor therapy. Recently, loss of methylthioadenosine phosphorylase (MTAP), a deletion frequently occurring in cancer, has been shown to create vulnerability to the inhibition of the protein arginine methyltransferase 5 (PRMT5). MTAP deficiency leads to accumulation of methylthioadenosine (MTA), which reduces PRMT5 activity, and thus, sensitizes the tumor cells to selective PRMT5 inhibitors (PRMT5i). PRMT5i are investigated as a new strategy to selectively kill MTAP-deficient tumor cells by blocking residual PRMT5 activity, but also to treat PRMT5-overexpressing tumors. Although many studies investigated the role of PRMT5 in cancer, only little data exist about the effect of PRMT5 inhibition on immune cells. As we could show that the tumor metabolite MTA suppresses T cells, we asked whether selective PRMT5 inhibition is detrimental for T-cell immune responses. Therefore, we examined the effect of the synthetic PRMT5 inhibitor EPZ015666 on human CD8+ T cells in direct comparison with the naturally occurring PRMT5-inhibiting molecule MTA. Both compounds reduced T-cell proliferation, viability, and functionality. In addition, T-cell metabolism was impaired upon PRMT5 inhibition. These effects coincided with the induction of p53 expression and reduced AKT/mTOR signaling. Our data clearly demonstrate that PRMT5 activity is involved in various cellular processes of human CD8+ T cells associated with essential T-cell functions. Therefore, not only tumor cells, but also antitumor immune responses, are compromised by PRMT5 inhibitors. This emphasizes the importance of considering side effects on the immune system when developing new strategies to specifically target not only MTAP-deficient tumors.

Authors with CRIS profile

Carolin Strobl Department of Medicine 5 – Haematology and Oncology Susann Hueber Institute of General Practice Martin Böttcher Department of Medicine 5 – Haematology and Oncology Dimitrios Mougiakakos Professur für Hämatologie/Onkologie mit dem Schwerpunkt Tumorimmunologie Andreas Mackensen Lehrstuhl für Innere Medizin V Simon Völkl Department of Medicine 5 – Haematology and Oncology

Involved external institutions

Universitätsklinikum Regensburg DE Germany (DE)

How to cite

APA:

Strobl, C., Schaffer, S., Haug, T., Peter, K., Singer, K., Böttcher, M.,... Völkl, S. (2020). Selective PRMT5 Inhibitors Suppress Human CD8+ T Cells by Upregulation of p53 and Impairment of the AKT Pathway Similar to the Tumor Metabolite MTA. Molecular Cancer Therapeutics, 19(2), 409-419. https://doi.org/10.1158/1535-7163.MCT-19-0189

MLA:

Strobl, Carolin, et al. "Selective PRMT5 Inhibitors Suppress Human CD8+ T Cells by Upregulation of p53 and Impairment of the AKT Pathway Similar to the Tumor Metabolite MTA." Molecular Cancer Therapeutics 19.2 (2020): 409-419.

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