当前位置: X-MOL 学术J. Thorac. Oncol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Impaired Cytolytic Activity and Loss of Clonal Neoantigens in Elderly Patients with Lung Adenocarcinoma
Journal of Thoracic Oncology ( IF 20.4 ) Pub Date : 2019-05-01 , DOI: 10.1016/j.jtho.2019.01.024
Zhihua Gong 1 , Qingzhu Jia 1 , Junying Chen 1 , Xinwei Diao 2 , Jianbao Gao 1 , Xinxin Wang 1 , Bo Zhu 3
Affiliation  

Introduction: Whether the efficacy of programmed death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) inhibitors declines with senescence remains controversial for lung adenocarcinoma (LUAD). Responsiveness to anti–PD‐1/PD‐L1 therapy is thought to rely on neoantigen exposure and immune elements in the tumor microenvironment. In this study, we explored the features of the tumor immune microenvironment in elderly patients with treatment‐naïve LUAD. Methods: Transcriptome profiles and clinical characteristics of patients with LUAD were retrieved from The Cancer Genome Atlas as a discovery cohort. Immune cell infiltration (quantified by a single‐sample gene set enrichment analysis), immunoregulatory molecule expression, and mutational patterns (from The Cancer Immunome Atlas) were compared between young and elderly patients. Immune cell infiltration was verified by immunohistochemistry using a validation cohort including 105 treatment‐naïve patients with LUAD. A tissue microarray consisting of 120 LUAD patients was used in the immunohistochemistry validation. Results: Activated CD8+ T cell numbers increased slightly with age, but cytolytic molecules in T cells (granzyme B [GZMB], perforin 1 [PRF1], granzyme A [GZMA], granzyme M [GZMM], and granulysin [GNLY]) gradually declined. PD‐L1 expression was not associated with age; however, a number of immunosuppressive elements beyond PD‐L1 were upregulated in aging patients, including regulatory T cells and co‐inhibitory molecules, for example, TIM‐3, TIGIT, and HHLA2. Finally, senescence was accompanied by a loss of clonal neoantigens, which is believed to be correlated with responsiveness to immune checkpoint inhibitors. Conclusions: Elderly patients were characterized by increased numbers of CD8+ T cells and impaired cytolytic molecule expression. The observed immune signature was also associated with a loss of clonal neoantigens and the accumulation of immunosuppressive elements. These findings show a unique immune microenvironment in senescence and support biomarker‐guided candidate identification for anti–PD‐1/PD‐L1 therapeutic strategies for elderly patients with LUAD.

中文翻译:

老年肺腺癌患者细胞溶解活性受损和克隆新抗原丢失

简介:程序性死亡 1 (PD-1)/程序性死亡配体 1 (PD-L1) 抑制剂的疗效是否随着衰老而下降,对于肺腺癌 (LUAD) 仍存在争议。对抗 PD-1/PD-L1 治疗的反应被认为依赖于肿瘤微环境中的新抗原暴露和免疫元素。在本研究中,我们探讨了初治 LUAD 老年患者的肿瘤免疫微环境特征。方法:从癌症基因组图谱中检索 LUAD 患者的转录组谱和临床特征作为发现队列。比较年轻和老年患者的免疫细胞浸润(通过单样本基因集富集分析量化)、免疫调节分子表达和突变模式(来自癌症免疫组图谱)。使用包含 105 名初治 LUAD 患者的验证队列通过免疫组织化学验证免疫细胞浸润。由 120 名 LUAD 患者组成的组织微阵列用于免疫组织化学验证。结果:活化的 CD8+ T 细胞数量随年龄增长略有增加,但 T 细胞中的溶细胞分子(颗粒酶 B [GZMB]、穿孔素 1 [PRF1]、颗粒酶 A [GZMA]、颗粒酶 M [GZMM] 和颗粒溶素 [GNLY])逐渐增加拒绝了。PD-L1 表达与年龄无关;然而,除了 PD-L1 之外的许多免疫抑制元件在老年患者中被上调,包括调节性 T 细胞和共抑制分子,例如 TIM-3、TIGIT 和 HHLA2。最后,衰老伴随着克隆新抗原的丧失,这被认为与对免疫检查点抑制剂的反应性相关。结论:老年患者的特征是 CD8+ T 细胞数量增加和细胞溶解分子表达受损。观察到的免疫特征还与克隆新抗原的丢失和免疫抑制元素的积累有关。这些发现显示了衰老过程中独特的免疫微环境,并支持生物标志物指导的 LUAD 老年患者抗 PD-1/PD-L1 治疗策略候选物鉴定。
更新日期:2019-05-01
down
wechat
bug