Identification and Validation of the Immune Subtypes of Lung Adenocarcinoma: Implications for Immunotherapy
Identification and Validation of the Immune Subtypes of Lung Adenocarcinoma: Implications for Immunotherapy
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肺腺癌免疫亚型的鉴定和验证：对免疫治疗的影响
DOI：
10.3389/fcell.2020.00550
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发表时间：
2020-07-03
影响因子：
5.5
通讯作者：
Xing, Ying
中科院分区：
文献类型：
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作者：
Song, Yang;Yan, Shi;Xing, Ying
肺腺癌（LUAD）是一种破坏性疾病，患者生存率低。癌症免疫疗法彻底改变了LUAD的治疗，但只有有限数量的患者对这种治疗有效。因此，阐明LUAD免疫异质性的工作对于开发具有更好疗效的新免疫策略至关重要。进行基于非负矩阵因子分解的去卷积，以识别癌症基因组图谱（TCGA）中489例LUAD患者的稳健聚类，并验证其在来自基因表达综合（GEO）的439例患者的独立LUAD队列中的再现性和稳定性。我们使用基于图学习的降维来可视化个体患者的分布。在这项研究中，四个可重复的免疫亚型，与不同的基因模块签名，临床病理特征，分子和细胞特征相关的簇1-4（C1-C4）进行了鉴定和验证。免疫冷亚型C3与LUAD患者的死亡事件、最晚期T分期、N分期、TNM分期和最差预后相关。此外，在C1-C4中，C3表现出最低的B细胞浸润水平、T细胞受体（TCR）库多样性和最高的新抗原水平和突变率。另一方面，免疫热亚型（C4）表现出最高的六种类型的浸润免疫细胞的浸润，以及最大的白细胞分数，TCR和B细胞受体（BCR）库的多样性。C1和C2亚型具有不同的临床病理和免疫学特征。最后，我们的研究发现了一个复杂的免疫景观，具有分散的免疫亚型谱。这项工作可能有助于为免疫决策提供信息，并为肺癌的治疗设计先进的免疫治疗策略。
Lung adenocarcinoma (LUAD) is a devastating disease with poor patient survival. Cancer immunotherapy has revolutionized the treatment of LUAD, but only a limited number of patients effectively respond to this treatment. Thus, the work to elucidate the LUAD immune heterogeneity could be crucial in developing new immunotherapeutic strategies with better efficacy. Non-negative matrix factorization-based deconvolution was performed to identify robust clusters of 489 LUAD patients in The Cancer Genome Atlas (TCGA) and verify their reproducibility and stability in an independent LUAD cohort of 439 patients from the Gene Expression Omnibus (GEO). We used the graph learning-based dimensionality reduction to visualize the distribution of individual patients. In this study, four reproducible immune subtypes, Clusters 1–4 (C1–C4) associated with distinct gene module signatures, clinicopathological features, molecular and cellular characteristics were identified and validated. The immune-cold subtype, C3, was associated with the Dead event, the most advanced T stage, N stage, TNM stage and the worst prognosis for LUAD patients. Moreover, C3 exhibited the lowest infiltrating levels of B cells, T cell receptor (TCR) repertoire diversity and the highest level of neoantigen and mutation rate among C1–C4. On the other hand, the immune-hot subtype (C4) exhibited the highest infiltration of six types of infiltrating immune cells as well as the greatest leukocyte fraction, TCR and B cell receptor (BCR) repertoire diversity. C1 and C2 subtypes showed diverse clinicopathological and immunological features. Finally, our investigations discovered a complex immune landscape with a scattered immune subtype profile. This work may help inform immunotherapeutic decision-making and design advanced immunotherapy strategies for the treatment of lung cancer.