我校新桥医院朱波教授团队在《Journal of Thoracic Oncology》发表研究成果——老年肺腺癌患者肿瘤微环境内新生抗原减少与抗瘤应答能力受损
发布人:zhangyilin 发布时间:9/23/2020 6:37:23 PM  浏览次数:10488次
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老年肺腺癌患者肿瘤微环境内新生抗原减少与抗瘤应答能力受损

 

龚志华,贾罄竹,朱波

 

全球范围内,非小细胞肺癌(Non-Small Cell Lung Cancer, NSCLC)的发病率和死亡率均位居恶性肿瘤之首。近年来,以免疫检查点抑制剂(Immune Checkpoint Blockade, ICB)为代表的免疫治疗取得突破性进展,极大的延长了NSCLC患者的生存时间。特别是由于ICB低毒性耐受性好的特点,其在老年患者(≥60岁)中的应用尤其受到关注。然而,临床研究结果初步提示,ICB药物应用于老年NSCLC患者治疗获益并不理想,而具体机制目前仍不清楚。

 

目前已知,肿瘤免疫微环境特征是实体肿瘤患者接受ICB治疗后是否能够获益的重要决定因素。而对于老年患者肿瘤免疫微环境特征的组成特征尚无系统的分析研究。因此,分析比较老年肿瘤患者肿瘤免疫微环境特征具有重要的临床意义。

 

本研究以NSCLC中腺癌为研究对象,利用TCGA公共数据库中574例患者基因组、转录组及临床随访数据为发现集,以第二附属医院肿瘤科120例患者组织标本及临床随访信息为验证集展开分析。研究结果表明,与非老年患者相比,老年患者肿瘤微环境内具有更多的活化型CD8+T细胞,但是PRF1、GZMA、GZMB与GNLY等重要的杀伤效应分子均随年龄的升高而降低,提示老年患者细胞毒性T细胞的杀伤功能明显减弱。此外,老年患者肿瘤内肿瘤突变负荷降低,特别是其中主克隆新生抗原负荷明显减少,不利于抗瘤免疫应答的有效激发。

 

本研究首次描述了老年肺腺癌患者肿瘤免疫微环境的特征,初步揭示了ICB治疗在老年NSCLC患者中疗效不佳的可能原因,为进一步发展有效的新型免疫联合治疗策略提供数据支撑。该研究结果于2019年2月发表于《Journal of Thoracic Oncology》(IF=13.44)

 

Impaired Cytolytic Activity and Loss of Clonal Neoantigens in Elderly Patients With Lung Adenocarcinoma

 

Zhihua Gong, Qingzhu Jia, Bo Zhu

 

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 CD8þ 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.

 


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