OPEN IN READ APP
JOURNAL ARTICLE

Selective PRMT5 inhibitors suppress human CD8+ T-cells by upregulation of p53 and impairment of the AKT pathway similar to the tumor metabolite MTA

Carolin Dorothea Strobl, Stefanie Schaffer, Tabea Haug, Simon Völkl, Katrin Peter, Katrin Singer, Martin Böttcher, Dimitrios Mougiakakos, Andreas Mackensen, Michael Aigner
Molecular Cancer Therapeutics 2019 November 11
31712395
Genetic alterations in tumor cells provide promising targets for anti-tumor 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. Though 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 if 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 to 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 anti-tumor 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.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Available on the App Store

Available on the Play Store
Remove bar
Read by QxMD icon Read
31712395
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"