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.
- Kirchner, M.
- Kluck, K.
- Brandt, R.
- Volckmar, A. L.
- Penzel, R.
- Kazdal, D.
- Endris, V.
- Neumann, O.
- Seker-Cin, H.
- Goldschmid, H.
- Glade, J.
- Allgauer, M.
- Kriegsmann, M.
- Winter, H.
- Muley, T.
- Perner, S.
- Frost, N.
- Reck, M.
- Frohling, S.
- Schirmacher, P.
- Thomas, M.
- Budczies, J.
- Christopoulos, P.
- Stenzinger, A.
Keywords
- EGFR exon 20 insertion
- ERBB2 exon 20 insertion
- immunosuppression
- lung adenocarcinoma
- tumor microenvironment
- personal fees from AstraZeneca, Bristol-Myers Squibb GmbH and Pfizer Pharma GmbH,
- outside the submitted work. VE reports personal fees from AstraZeneca, Bayer,
- Lilly, BMS, MSD Sharp, Novartis and Thermo Fisher, outside the submitted work. TM
- reports grants and non-financial support from Roche Diagnostics GmbH, Penzberg,
- Germany, outside the submitted work
- in addition, TM has a patent WO2019158460
- pending, a patent WO2019211418 pending, a patent WO2019215223 pending, a patent
- EP3391053 issued and a patent EP3365679 pending. NF reports personal fees and
- travel grants from AbbVie, AstraZeneca, Boehringer Ingelheim, BMS and Takeda,
- outside the submitted work, and personal fees from Amgen, BerlinChemie, BeiGene,
- MSD, Novartis, Pfizer, Roche and Sanofi, outside the submitted work. MR reports
- personal fees from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Lilly, Merck,
- MSD, Novartis, Pfizer, Roche and Samsung, outside the submitted work. SF reports
- personal fees from Amgen, Bayer, Eli Lilly and Roche
- grants from AstraZeneca and
- Pfizer
- and grants and personal fees from PharmaMar, outside the submitted work.
- PS reports grants from QuIP, during the conduct of the study
- grants and personal
- fees from BMS, MSD, Roche, AstraZeneca, Novartis and Pfizer
- personal fees from
- Chugai, AbbVie and Ipsen
- and grants from Sanofi-Aventis, Illumina and Thermo
- Fisher, outside the submitted work. MT reports personal fees from AbbVie, Lilly
- and Takeda
- grants, personal fees and non-financial support from BMS
- personal
- fees and non-financial support from Boehringer, MSD and Novartis
- grants and
- personal fees from Celgene and Roche
- and grants from AstraZeneca, outside the
- submitted work. JB reports grants from German Cancer Aid, outside the submitted
- work. PC reports grants and personal fees from AstraZeneca, Novartis, Roche and
- Takeda and personal fees from Boehringer Ingelheim, Chugai and Pfizer, outside
- the submitted work. AS reports personal fees from AstraZeneca, MSD, Takeda,
- Seattle Genetics, Novartis, Illumina, Thermo Fisher, Eli Lily and Takeda
- grants
- and personal fees from Bayer and BMS
- and grants from Chugai, outside the
- submitted work. All other authors have declared no conflicts of interest.
