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

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.

Automated summary

Loss of MTAP in the chromosomal region 9p21 leads to reduced tumor-infiltrating lymphocytes and resistance to immune checkpoint inhibitor therapy. The loss of MTAP causes accumulation of methylthioadenosine (MTA), which impairs T cell function. Administration of MTA-depleting enzymes reverses the immunosuppressive effect and increases tumor-infiltrating lymphocytes, inhibiting tumor growth. Targeting MTA degradation may enhance the effectiveness of immune checkpoint inhibitor therapy in patients with 9p21/MTAP loss.