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

M. Kirchner; K. Kluck; R. Brandt; A. L. Volckmar; R. Penzel; D. Kazdal; V. Endris; O. Neumann; H. Seker-Cin; H. Goldschmid; J. Glade; M. Allgäuer; M. Kriegsmann; H. Winter; T. Muley; S. Perner; N. Frost; M. Reck; S. Fröhling; P. Schirmacher; M. Thomas; J. Budczies; P. Christopoulos; A. Stenzinger

doi:10.1016/j.esmoop.2021.100253

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

M. Kirchner, K. Kluck, R. Brandt, A. L. Volckmar, R. Penzel, D. Kazdal, V. Endris, O. Neumann, H. Seker-Cin, H. Goldschmid, J. Glade, M. Allgäuer, M. Kriegsmann, H. Winter, T. Muley, S. Perner, N. Frost, M. Reck, S. Fröhling, P. SchirmacherM. Thomas, J. Budczies, P. Christopoulos, A. Stenzinger^*

^*Corresponding author for this work

31 Citations (Scopus)

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 = 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.

Original language	English
Article number	100253
Journal	ESMO Open
Volume	6
Issue number	5
DOIs	https://doi.org/10.1016/j.esmoop.2021.100253
Publication status	Published - 10.2021

Funding

This work was supported by the German Center for Lung Research (Deutsches Zentrum für Lungenforschung, DZL) (no grant number). 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. We thank all technical assistants of the Center for Molecular Pathology (CMP) Heidelberg for expert handling of tissue and for technical support. This work was supported by the German Center for Lung Research (Deutsches Zentrum f?r Lungenforschung, DZL) (no grant number). 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. Data are available upon reasonable request.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1016/j.esmoop.2021.100253

Cite this

Kirchner, M., Kluck, K., Brandt, R., Volckmar, A. L., Penzel, R., Kazdal, D., Endris, V., Neumann, O., Seker-Cin, H., Goldschmid, H., Glade, J., Allgäuer, M., Kriegsmann, M., Winter, H., Muley, T., Perner, S., Frost, N., Reck, M., Fröhling, S., ... Stenzinger, A. (2021). The immune microenvironment in EGFR- and ERBB2-mutated lung adenocarcinoma. ESMO Open, 6(5), Article 100253. https://doi.org/10.1016/j.esmoop.2021.100253

@article{3acefb98043f47b78abdfda15a32332b,

title = "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 = 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.",

author = "M. Kirchner and K. Kluck and R. Brandt and Volckmar, \{A. L.\} and R. Penzel and D. Kazdal and V. Endris and O. Neumann and H. Seker-Cin and H. Goldschmid and J. Glade and M. Allg{\"a}uer and M. Kriegsmann and H. Winter and T. Muley and S. Perner and N. Frost and M. Reck and S. Fr{\"o}hling and P. Schirmacher and M. Thomas and J. Budczies and P. Christopoulos and A. Stenzinger",

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = oct,

doi = "10.1016/j.esmoop.2021.100253",

language = "English",

volume = "6",

journal = "ESMO Open",

issn = "2059-7029",

publisher = "Elsevier B.V.",

number = "5",

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Kirchner, M, Kluck, K, Brandt, R, Volckmar, AL, Penzel, R, Kazdal, D, Endris, V, Neumann, O, Seker-Cin, H, Goldschmid, H, Glade, J, Allgäuer, M, Kriegsmann, M, Winter, H, Muley, T, Perner, S, Frost, N, Reck, M, Fröhling, S, Schirmacher, P, Thomas, M, Budczies, J, Christopoulos, P & Stenzinger, A 2021, 'The immune microenvironment in EGFR- and ERBB2-mutated lung adenocarcinoma', ESMO Open, vol. 6, no. 5, 100253. https://doi.org/10.1016/j.esmoop.2021.100253

TY - JOUR

T1 - The immune microenvironment in EGFR- and ERBB2-mutated lung adenocarcinoma

AU - Kirchner, M.

AU - Kluck, K.

AU - Brandt, R.

AU - Volckmar, A. L.

AU - Penzel, R.

AU - Kazdal, D.

AU - Endris, V.

AU - Neumann, O.

AU - Seker-Cin, H.

AU - Goldschmid, H.

AU - Glade, J.

AU - Allgäuer, M.

AU - Kriegsmann, M.

AU - Winter, H.

AU - Muley, T.

AU - Perner, S.

AU - Frost, N.

AU - Reck, M.

AU - Fröhling, S.

AU - Schirmacher, P.

AU - Thomas, M.

AU - Budczies, J.

AU - Christopoulos, P.

AU - Stenzinger, A.

PY - 2021/10

Y1 - 2021/10

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85120456571

U2 - 10.1016/j.esmoop.2021.100253

DO - 10.1016/j.esmoop.2021.100253

M3 - Journal articles

C2 - 34487971

AN - SCOPUS:85120456571

SN - 2059-7029

VL - 6

JO - ESMO Open

JF - ESMO Open

IS - 5

M1 - 100253

ER -

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

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