Related Experiment Video
Updated: Oct 21, 2025
Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
The immune microenvironment in EGFR- and ERBB2-mutated lung adenocarcinoma
M Kirchner1, K Kluck2, R Brandt1
1Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Background:
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.
Materials And Methods:
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.
Results:
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.
Conclusions:
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.
Insights
This study reveals distinct immune profiles in lung adenocarcinomas with EGFR and HER2 exon 20 mutations, identifying potential therapeutic targets. Understanding these immune characteristics is crucial for developing effective non-small-cell lung cancer treatments.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Non-small-cell lung cancer (NSCLC) with actionable driver mutations has improved outcomes with targeted therapies.
- However, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 gene (HER2/ERBB2) exon 20 insertions (Ex20mut) show poor response to current treatments.
- The immune biology underlying these specific mutations is poorly understood.
Purpose of the Study:
- To investigate the immune microenvironment in NSCLC with EGFR and HER2 Ex20mut.
- To compare immune profiles between different EGFR mutation subtypes and wild-type tumors.
- To identify potential therapeutic targets based on gene expression differences.
Main Methods:
- Messenger RNA expression profiling of lung adenocarcinomas (ADCs) with ERBB2 (n=19), EGFR Ex20mut (n=13), classical EGFR mutations (n=40), and wild-type (n=26).
- Focus on immunologically relevant transcripts and estimation of tumor-infiltrating immune cells from gene expression profiles.
- Differential gene expression analysis to identify significant molecular changes.
Main Results:
- Cytotoxic and Th1 cells were significantly lower in EGFR-mutated tumors, particularly EGFR-Ex20mut compared to wild-type.
- Identified differentially expressed genes, with VHL and JAK1 overexpression in ERBB2-Ex20mut and EGFR-Ex20mut tumors.
- RIPK1 and STK11IP showed highest expression in ERBB2-Ex20mut tumors, indicating specific molecular alterations.
Conclusions:
- Targeted gene expression profiling can characterize the tumor microenvironment from routine biopsies.
- ERBB2-Ex20mut and EGFR-Ex20mut lung ADCs exhibit significant immune reactivity and immunosuppressive characteristics.
- These findings support clinical evaluation of immune-modulators combined with immune checkpoint inhibitors for these NSCLC subtypes.
More Related Videos
09:38Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
Published on: June 26, 2019
13:34A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
Related Concept Videos
02:38Mitogens and the Cell Cycle
02:17The Tumor Microenvironment
01:22Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal