AI Article Synopsis
- The chromosomal region 9p21, which includes the tumor suppressors CDKN2A/B and the MTAP gene, is frequently deleted in cancers and is linked to lower levels of tumor-infiltrating lymphocytes (TILs) and resistance to immune therapies.
- Recent findings indicate that the loss of MTAP, rather than CDKN2A/B, contributes to worse outcomes in immune checkpoint inhibitor (ICI) treatment due to the build-up of methylthioadenosine (MTA), which negatively affects T cell function.
- Using MTA-depleting enzymes can reverse these negative effects, leading to increased TILs and decreased tumor growth, suggesting that these therapies could enhance the effectiveness of ICI
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10591910 | PMC |
| http://dx.doi.org/10.1016/j.ccell.2023.09.005 | DOI Listing |
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