Enzyme-mediated depletion of methylthioadenosine restores T cell function in MTAP-deficient tumors and reverses immunotherapy resistance.

Abstract

Chromosomal region 9p21 containing tumor suppressors CDKN2A/B and methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic deletions in cancer. 9p21 loss is correlated with reduced tumor-infiltrating lymphocytes (TILs) and resistance to immune checkpoint inhibitor (ICI) therapy. Previously thought to be caused by CDKN2A/B loss, we now show that it is loss of MTAP that leads to poor outcomes on ICI therapy and reduced TIL density. MTAP loss causes accumulation of methylthioadenosine (MTA) both intracellularly and extracellularly and profoundly impairs T cell function via the inhibition of protein arginine methyltransferase 5 (PRMT5) and by adenosine receptor agonism. Administration of MTA-depleting enzymes reverses this immunosuppressive effect, increasing TILs and drastically impairing tumor growth and importantly, synergizes well with ICI therapy. As several studies have shown ICI resistance in 9p21/MTAP null/low patients, we propose that MTA degrading therapeutics may have substantial therapeutic benefit in these patients by enhancing ICI effectiveness.

• Authors: Donjeta Gjuka, Elio Adib, Kendra Garrison, Jianfeng Chen, Yuxue Zhang, Wenjiao Li, Daniel Boutz, Candice Lamb, Yuri Tanno, Amin Nassar, Talal El Zarif, Neil Kale, Mehrdad Rakaee, Tarek H Mouhieddine, Sarah Abou Alaiwi, Alexander Gusev, Thomas Rogers, Jianjun Gao, George Georgiou, David J Kwiatkowski, Everett Stone
• Journal: Cancer cell (Cancer Cell) Vol. 41 Issue 10 Pg. 1774-1787.e9 (10 09 2023) ISSN: 1878-3686 [Electronic] United States
• PMID: 37774699 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• 5'-methylthioadenosine phosphorylase
• Purine-Nucleoside Phosphorylase
• PRMT5 protein, human
• Protein-Arginine N-Methyltransferases

Topics

• Humans
• T-Lymphocytes (metabolism)
• Neoplasms (drug therapy, genetics)
• Purine-Nucleoside Phosphorylase (genetics)
• Immunotherapy
• Protein-Arginine N-Methyltransferases (genetics)