Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
ESMO Open. 2021 Oct;6(5):100253. doi: 10.1016/j.esmoop.2021.100253. Epub 2021 Sep 3.
Targeted therapies have improved survival and quality of life for patients with non-small-cell lung cancer with actionable driver mutations. However, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 gene (HER2, also known as ERBB2) exon 20 insertions (Ex20mut) are characterized by a poor response to currently approved tyrosine kinase inhibitors and immunotherapies. The underlying immune biology is not well understood.
We carried out messenger RNA expression profiling of lung adenocarcinomas (ADCs) with ERBB2 (n = 19) and EGFR exon 20-insertion mutations (n = 13) and compared these to tumors with classical EGFR mutations (n = 40, affecting EGFR exons 18, 19 or 21) and EGFR/ERBB2 mutation-negative lung ADC (EGFR/ERBB2wt, n = 26) focusing on immunologically relevant transcripts. Tumor-infiltrating immune cells were estimated from gene expression profiles.
Cytotoxic cells were significantly lower in EGFR-mutated tumors regardless of the affected exon, while Th1 cells were significantly lower in EGFR-Ex20mut compared to EGFR/ERBB2wt tumors. We assessed the differentially expressed genes of ERBB2-Ex20mut and EGFR-Ex20mut tumors compared to EGFR-Ex18/19/21mut and EGFR/ERBB2wt tumors. Of these, the genes GUSB, HDAC11, IFNGR2, PUM1, RASGRF1 and RBL2 were up-regulated, while a lower expression of CBLC, GBP1, GBP2, GBP4 and MYC was observed in all three comparison groups. The omnibus test revealed 185 significantly (FDR = 5%) differentially expressed genes and we found these four most significant gene expression changes in the study cohort: VHL and JAK1 were overexpressed in ERBB2-Ex20mut and EGFR-Ex20mut tumors compared to both EGFR-Ex18/19/21mut and EGFR/ERBB2wt tumors. RIPK1 and STK11IP showed the highest expression in ERBB2-Ex20mut tumors.
Targeted gene expression profiling is a promising tool to read out the characteristics of the tumor microenvironment from routine diagnostic lung cancer biopsies. Significant immune reactivity and specific immunosuppressive characteristics in ERBB2-Ex20mut and EGFR-Ex20mut lung ADC with at least some degree of immune infiltration support further clinical evaluation of immune-modulators as partners of immune checkpoint inhibitors in such tumors.
针对具有可操作驱动突变的非小细胞肺癌患者，靶向治疗已改善了其生存和生活质量。然而，表皮生长因子受体（EGFR）和人表皮生长因子受体 2 基因（HER2，也称为 ERBB2）外显子 20 插入（Ex20mut）的特征是对目前批准的酪氨酸激酶抑制剂和免疫疗法反应不佳。其潜在的免疫生物学尚不清楚。
我们对 ERBB2（n=19）和 EGFR 外显子 20 插入突变（n=13）的肺腺癌（ADC）进行了信使 RNA 表达谱分析，并将其与具有经典 EGFR 突变的肿瘤（n=40，影响 EGFR 外显子 18、19 或 21）和 EGFR/ERBB2 突变阴性的肺 ADC（EGFR/ERBB2wt，n=26）进行了比较，重点关注免疫相关的转录物。从基因表达谱中估计了肿瘤浸润免疫细胞。
无论受影响的外显子如何，EGFR 突变肿瘤中的细胞毒性细胞均明显降低，而与 EGFR/ERBB2wt 肿瘤相比，EGFR-Ex20mut 中的 Th1 细胞明显降低。我们评估了 ERBB2-Ex20mut 和 EGFR-Ex20mut 肿瘤与 EGFR-Ex18/19/21mut 和 EGFR/ERBB2wt 肿瘤相比差异表达的基因。在这些基因中，GUSB、HDAC11、IFNGR2、PUM1、RASGRF1 和 RBL2 上调，而 GBP1、GBP2、GBP4 和 MYC 的表达水平在所有三组比较中均降低。总体检验显示有 185 个基因显著（FDR=5%）差异表达，我们在研究队列中发现了这四个最显著的基因表达变化：与 EGFR-Ex18/19/21mut 和 EGFR/ERBB2wt 肿瘤相比，VHL 和 JAK1 在 ERBB2-Ex20mut 和 EGFR-Ex20mut 肿瘤中过度表达。RIPK1 和 STK11IP 在 ERBB2-Ex20mut 肿瘤中表达最高。
靶向基因表达谱分析是一种很有前途的工具，可以从常规诊断性肺癌活检中读取肿瘤微环境的特征。在至少有一定程度免疫浸润的 ERBB2-Ex20mut 和 EGFR-Ex20mut 肺 ADC 中，显著的免疫反应性和特定的免疫抑制特征支持进一步评估免疫调节剂作为此类肿瘤免疫检查点抑制剂的伴侣的临床应用。
