2023-10-09 テキサス大学オースチン校(UT Austin)
◆多くのがんは9p21というDNA領域を削除し、これががん細胞が免疫から逃れる手助けをしています。この薬物はMTAと呼ばれる有害な化合物のレベルを正常に戻し、免疫システムを再活性化させます。これはがん治療の革命的な可能性を持つ研究です。
<関連情報>
- https://news.utexas.edu/2023/10/09/cancer-drug-restores-immune-systems-ability-to-fight-tumors/
- https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00321-5
酵素を介したメチルチオアデノシンの枯渇はMTAP欠損腫瘍のT細胞機能を回復させ、免疫療法抵抗性を逆転させる Enzyme-mediated depletion of methylthioadenosine restores T cell function in MTAP-deficient tumors and reverses immunotherapy resistance
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
Cancer Cell Published:September 28, 2023
DOI:https://doi.org/10.1016/j.ccell.2023.09.005
Highlights
•MTAP loss increases MTA levels and ICI failure in melanoma and urothelial tumors
•Excess MTA in the TME impairs CD4+ and CD8+ T cells via ADO agonism and PRMT5 inhibition
•PEG-MTAP delivery to MTAP-/- tumors controls tumor growth dependent of CD8+ T cells
•MTAP and IO combination therapy is proposed for the treatment of MTAP-deficient cancers
Summary
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.
