The immune microenvironment in EGFR- and ERBB2-mutated lung adenocarcinoma

Martina Kirchner ,Thomas Muley ,Sven Perner ,Nikolaj Frost ,Stefan Fröhling ,Hannah Goldschmid ,Olaf Neumann ,Anna‐Lena Volckmar ,Hauke Winter ,Martin Reck ,Huriye Şeker-Cin ,Peter Schirmacher ,Roland Penzel ,Mark Kriegsmann ,Michael Thomas ,Daniel Kazdal ,Volker Endris ,Michael Allgäuer ,Jan Budczies ,Klaus Kluck ,Julia Glade ,Regine Brandt ,Petros Christopoulos ,Albrecht Stenzinger

doi:10.1016/j.esmoop.2021.100253

Abstract

BackgroundTargeted 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 methodsWe 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.ResultsCytotoxic 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.ConclusionsTargeted 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.

Highlights

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide.[1]
Exon 20 insertions, which account for 1%10% of all epidermal growth factor receptor (EGFR) mutations, define a distinct subset of lung ADC characterized by a poor response to all currently approved EGFR-tyrosine kinase inhibition (TKI).[4,5]
12-bp in-frame insertions and other mutations of the human epidermal growth factor receptor 2 gene (HER2, known as ERBB2) are oncogenic drivers in 2%-3% of NSCLC6-8 that are resistant to EGFR-TKIs and difficult to target with specific ERBB2 and dual EGFR/ ERBB2 inhibitors, as they result in steric hindrance of the drug-binding pocket.[9,10]

Summary

Introduction

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide.[1]. Mainly tyrosine kinase inhibition (TKI), have improved the overall survival and quality of life for patients with actionable driver mutations.[2] Epidermal growth factor receptor (EGFR)-activating mutations represent the most frequent targetable alteration with a prevalence of nearly 20% in Caucasians with lung adenocarcinomas (ADCs) and show sensitivity to various TKIs.[3] exon 20 insertions, which account for 1%10% of all EGFR mutations, define a distinct subset of lung ADC characterized by a poor response to all currently approved EGFR-TKIs.[4,5] 12-bp in-frame insertions and other mutations of the human epidermal growth factor receptor 2 gene (HER2, known as ERBB2) are oncogenic drivers in 2%-3% of NSCLC6-8 that are resistant to EGFR-TKIs and difficult to target with specific ERBB2 and dual EGFR/ ERBB2 inhibitors, as they result in steric hindrance of the drug-binding pocket.[9,10].

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Results

Conclusion