Faculty, Staff and Student Publications

Language

English

Publication Date

10-9-2023

Journal

Cancer Cell

DOI

10.1016/j.ccell.2023.09.005

PMID

37774699

PMCID

PMC10591910

PubMedCentral® Posted Date

10-9-2024

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Humans, T-Lymphocytes, Neoplasms, Purine-Nucleoside Phosphorylase, Immunotherapy, Protein-Arginine N-Methyltransferases

Published Open-Access

yes

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