INTRODUCTION Tumor infiltrating immune cells are key elements of the tumor microenvironment and mediate the anti-tumor effects of immunotherapy. The aim of the study was to characterize patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to tumor mutations and clinicopathological parameters. METHODS Lymphocytes (CD3+, CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+) and PD-L1+ were annotated on a tissue microarray including 357 operated NSCLC cases. Somatic mutations and tumor mutational burden were analyzed by targeted sequencing for 82 genes, and transcriptomic immune patterns were established in 197 patients based on RNAseq data. RESULTS We identified somatic mutations (TP53, NF1, KEAP1, CSMD3, LRP1B) that correlated with specific immune cell infiltrates. Hierarchical clustering revealed four immune classes: with (1) high immune cell infiltration ("inflamed"), (2) low immune cell infiltration ("desert"), (3) a mixed phenotype, and (4) a new phenotype with an overall muted inflammatory cell pattern but with an imprint of NK and plasma cells. This latter class exhibited low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, TGFB1), but was linked to better survival and therefore designated "oasis". Otherwise, the four immune classes were not related to the presence of specific mutations (EGFR, KRAS, TP53) or histologic subtypes. Importantly, the identified immune classes based on tissue staining could not be translated into RNA expression signatures extracted from crude NSCLC tissue. CONCLUSION We present a compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC and identified the novel immune class "oasis". The immune classification helps to better define the immunogenic potency of NSCLC in the era of immunotherapy.

中文翻译：

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非小细胞肺癌（NSCLC）免疫细胞浸润模式的表征。


引言肿瘤浸润免疫细胞是肿瘤微环境的关键要素，介导免疫治疗的抗肿瘤作用。该研究的目的是确定非小细胞肺癌（NSCLC）中免疫细胞浸润模式与肿瘤突变和临床病理参数的关系。方法 在包含 357 例手术 NSCLC 病例的组织微阵列上对淋巴细胞（CD3+、CD4+、CD8+、CD20+、FOXP3+、CD45RO+）、巨噬细胞（CD163+）、浆细胞（CD138+）、NK 细胞（NKp46+）和 PD-L1+ 进行注释。通过 82 个基因的靶向测序分析体细胞突变和肿瘤突变负荷，并根据 RNAseq 数据在 197 名患者中建立转录组免疫模式。结果我们确定了与特定免疫细胞浸润相关的体细胞突变（TP53、NF1、KEAP1、CSMD3、LRP1B）。层次聚类揭示了四种免疫类别：（1）高免疫细胞浸润（“发炎”），（2）低免疫细胞浸润（“沙漠”），（3）混合表型，以及（4）具有总体上炎症细胞模式减弱，但带有 NK 和浆细胞的印记。后一类表现出免疫反应相关基因（例如CXCL9、GZMB、INFG、TGFB1）的低表达，但与更好的生存相关，因此被称为“绿洲”。除此之外，四种免疫类别与特定突变（EGFR、KRAS、TP53）或组织学亚型的存在无关。重要的是，基于组织染色确定的免疫类别无法转化为从粗制 NSCLC 组织中提取的 RNA 表达特征。结论 我们在 NSCLC 的分子和临床背景下进行了区室特异性免疫细胞分析，并确定了新的免疫类别“绿洲”。 免疫分类有助于更好地定义免疫治疗时代NSCLC的免疫原性效力。