Kelly Gregory M, Al-Ejeh Fares, McCuaig Robert, Casciello Francesco, Ahmad Kamal Nabilah, Ferguson Blake, Pritchard Antonia L, Ali Sayed, Silva Ines P, Wilmott James S, Long Georgina V, Scolyer Richard A, Rao Sudha, Hayward Nicholas K, Gannon Frank, Lee Jason S
QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
School of Medicine, University of Queensland, Herston, Queensland, Australia.
Clin Cancer Res. 2021 May 1;27(9):2624-2635. doi: 10.1158/1078-0432.CCR-20-3463. Epub 2021 Feb 15.
G9a histone methyltransferase exerts oncogenic effects in several tumor types and its inhibition promotes anticancer effects. However, the impact on checkpoint inhibitor blockade response and the utility of G9a or its target genes as a biomarker is poorly studied. We aimed to examine whether G9a inhibition can augment the efficacy of checkpoint inhibitor blockade and whether , a G9a target gene, can predict treatment response.
Clinical potential of LC3B as a biomarker of checkpoint inhibitor blockade was assessed using patient samples including tumor biopsies and circulating tumor cells from liquid biopsies. Efficacy of G9a inhibition to enhance checkpoint inhibitor blockade was examined using a mouse model.
Patients with melanoma who responded to checkpoint inhibitor blockade were associated with not only a higher level of tumor LC3B but also a higher proportion of cells expressing LC3B. A higher expression of or LC3B protein was associated with longer survival and lower incidence of acquired resistance to checkpoint inhibitor blockade, suggesting LC3B as a potential predictive biomarker. We demonstrate that G9a histone methyltransferase inhibition is able to not only robustly induce LC3B level to augment the efficacy of checkpoint inhibitor blockade, but also induces melanoma cell death.
Checkpoint inhibitor blockade response is limited to a subset of the patient population. These results have implications for the development of LC3B as a predictive biomarker of checkpoint inhibitor blockade to guide patient selection, as well as G9a inhibition as a strategy to extend the proportion of patients responding to immunotherapy.
G9a组蛋白甲基转移酶在多种肿瘤类型中发挥致癌作用，对其抑制可促进抗癌效果。然而，其对检查点抑制剂阻断反应的影响以及G9a或其靶基因作为生物标志物的效用研究较少。我们旨在研究G9a抑制是否能增强检查点抑制剂阻断的疗效，以及G9a靶基因LC3B是否能预测治疗反应。
使用包括肿瘤活检和液体活检中的循环肿瘤细胞在内的患者样本，评估LC3B作为检查点抑制剂阻断生物标志物的临床潜力。使用小鼠模型研究G9a抑制增强检查点抑制剂阻断的疗效。
对检查点抑制剂阻断有反应的黑色素瘤患者不仅肿瘤LC3B水平较高，而且表达LC3B的细胞比例也较高。较高的LC3B或LC3B蛋白表达与更长的生存期和更低的获得性检查点抑制剂阻断耐药发生率相关，表明LC3B是一种潜在的预测生物标志物。我们证明，G9a组蛋白甲基转移酶抑制不仅能够强烈诱导LC3B水平以增强检查点抑制剂阻断的疗效，还能诱导黑色素瘤细胞死亡。
检查点抑制剂阻断反应仅限于一部分患者群体。这些结果对于将LC3B开发为检查点抑制剂阻断的预测生物标志物以指导患者选择，以及将G9a抑制作为扩大免疫治疗反应患者比例的策略具有重要意义。
