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

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.

Informations de copyright

Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Disclosure MKi reports grants from QuIP, outside the submitted work. DK reports 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.