Department of Chemical Engineering, University of Texas, Austin, TX, USA.
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Lank Genitourinary Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Cancer Cell. 2023 Oct 9;41(10):1774-1787.e9. doi: 10.1016/j.ccell.2023.09.005. Epub 2023 Sep 28.
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.
包含肿瘤抑制因子 CDKN2A/B 和甲基硫腺苷磷酸化酶（MTAP）的 9p21 染色体区域是癌症中最常见的遗传缺失之一。9p21 的缺失与浸润肿瘤的淋巴细胞（TILs）减少以及对免疫检查点抑制剂（ICI）治疗的耐药性相关。以前认为是由于 CDKN2A/B 的缺失引起的，我们现在表明，正是 MTAP 的缺失导致 ICI 治疗效果不佳和 TIL 密度降低。MTAP 的缺失导致甲基硫腺苷（MTA）在细胞内和细胞外积累，并通过抑制蛋白质精氨酸甲基转移酶 5（PRMT5）和通过腺苷受体激动作用严重损害 T 细胞功能。施用消耗 MTA 的酶可逆转这种免疫抑制作用，增加 TILs，并严重抑制肿瘤生长，重要的是，与 ICI 治疗具有良好的协同作用。由于几项研究表明 9p21/MTAP 缺失/低的患者存在 ICI 耐药性，我们提出，通过增强 ICI 的有效性，消耗 MTA 的治疗药物可能会为这些患者带来实质性的治疗益处。
