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

Abstract

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 ¼ 19) and EGFR exon 20-insertion mutations (n ¼ 13) and compared these to tumors with classical EGFR mutations (n ¼ 40, affecting EGFR exons 18, 19 or 21) and EGFR/ERBB2 mutation-negative lung ADC (EGFR/ ERBB2wt, n ¼ 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 ¼ 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.

Molecular Landscape of ERBB2 Alterations in 14,956 Solid Tumors

“…ERBB2 exon 20 insertions were reported as analogous to EGFR exon 20 insertions and associated with primary resistance to currently approved tyrosine kinase inhibitors because of steric hindrance in the drug-binding pocket and a poor response to immunotherapies in lung adenocarcinoma ( 27 , 28 ) _ENREF_24. In further analysis, ERBB2 exon 20-mutated tumors exhibited overexpression of RIPK1 and STK11IP and a decrease of cytotoxic natural killer cells ( 28 ). We also found lung cancer patients with ERBB2 -mutant have lower TMB than non- ERBB2 mutant patients ( p = 0.048).…”

“…The most frequently appearing subtypes were Y772_A775dup (82/93, 88.2%) and p.G778_P780dup (8/93, 8.6%). ERBB2 exon 20 insertions were reported as analogous to EGFR exon 20 insertions and associated with primary resistance to currently approved tyrosine kinase inhibitors because of steric hindrance in the drug-binding pocket and a poor response to immunotherapies in lung adenocarcinoma (27,28) _ENREF_24. In further analysis, ERBB2 exon 20-mutated tumors exhibited overexpression of RIPK1 and STK11IP and a decrease of cytotoxic natural killer cells (28).…”

Oral Squamous Cell Carcinoma in Young Patients Show Higher Rates of EGFR Amplification: Implications for Novel Personalized Therapy

“…These findings imply that both EGFR amplification and elevated EGFR protein levels may be used as a biomarker to select patients likely to respond to EGFR inhibitors. Kirchner et al (55) and Matsumoto et al (56) have described a 'cold' immunophenotype in EGFR-mutant NSCLC. Our analysis demonstrates that young patients with OSCC appear to have low levels of TILs irrespective of EGFR amplification status.…”

“…Kirchner et al. ( 55 ) and Matsumoto et al. ( 56 ) have described a ‘cold’ immunophenotype in EGFR -mutant NSCLC.…”

“…Cetuximab is a monoclonal antibody that prevents dimerization of EGFR by binding to its extracellular domain, inhibiting receptor-ligand interactions ( 61 , 64 ), whereas afatinib is a second-generation TKI that irreversibly binds the intracellular tyrosine kinase domain of EGFR ( 61 , 65 ). Afatinib has been shown to be more efficacious than chemotherapy for the treatment of NSCLCs harboring specific EGFR mutations ( 55 , 56 , 66 ). However, data on the use of afatinib for the treatment of HNSCC is still emerging, although in clinical trials, afatinib has demonstrated higher activity versus other EGFR TKIs ( 67 ).…”