Institute of Cancer, Xinqiao Hospital of The Third Military Medical University, Chongqing, China.
Department of Pathology, Xinqiao Hospital of The Third Military Medical University, Chongqing, China.
J Thorac Oncol. 2019 May;14(5):857-866. doi: 10.1016/j.jtho.2019.01.024. Epub 2019 Feb 12.
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.
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.
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.
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.
程序性死亡受体 1（PD-1）/程序性死亡配体 1（PD-L1）抑制剂的疗效是否会随衰老而下降，这在肺腺癌（LUAD）中仍存在争议。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成分。在这项研究中，我们探索了治疗初治 LUAD 的老年患者肿瘤免疫微环境的特征。
从癌症基因组图谱（TCGA）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之间的免疫细胞浸润（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（来自癌症免疫图谱）。使用包括 105 例治疗初治 LUAD 患者的验证队列来验证免疫细胞浸润。使用包含 120 例 LUAD 患者的组织微阵列进行免疫组织化学验证。
激活的 CD8 T 细胞数量随年龄略有增加，但 T 细胞中的细胞毒性分子（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]）逐渐下降。PD-L1 表达与年龄无关；然而，在衰老患者中，除了 PD-L1 之外，许多免疫抑制性成分上调，包括调节性 T 细胞和共抑制分子，例如 TIM-3、TIGIT 和 HHLA2。最后，衰老伴随着克隆性新抗原的丧失，这被认为与免疫检查点抑制剂的反应相关。
老年患者的特点是 CD8 T 细胞数量增加和细胞毒性分子表达受损。观察到的免疫特征也与克隆性新抗原的丧失和免疫抑制性成分的积累有关。这些发现显示了衰老中独特的免疫微环境，并支持基于生物标志物的候选物识别，以用于老年 LUAD 患者的抗 PD-1/PD-L1 治疗策略。
