Interleukin-1 alpha increases anti-tumor efficacy of cetuximab in head and neck squamous cell carcinoma

Madelyn Espinosa-Cotton, Samuel N. Rodman, Kathleen A. Ross, Isaac J. Jensen, Kenley Sangodeyi-Miller, Ayana J. McLaren, Rachel A. Dahl, Katherine N. Gibson-Corley, Adam T. Koch, Yang-Xin Fu, Vladimir P. Badovinac, Douglas Laux, Balaji Narasimhan, Andrean L. Simons

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: Despite the high prevalence of epidermal growth factor receptor (EGFR) overexpression in head and neck squamous cell carcinomas (HNSCCs), incorporation of the EGFR inhibitor cetuximab into the clinical management of HNSCC has not led to significant changes in long-term survival outcomes. Therefore, the identification of novel therapeutic approaches to enhance the clinical efficacy of cetuximab could lead to improved long-term survival for HNSCC patients. Our previous work suggests that EGFR inhibition activates the interleukin-1 (IL-1) pathway via tumor release of IL-1 alpha (IL-1α), although the clinical implications of activating this pathway are unclear in the context of cetuximab therapy. Given the role of IL-1 signaling in anti-tumor immune response, we hypothesized that increases in IL-1α levels would enhance tumor response to cetuximab. Methods: Parental and stable myeloid differentiation primary response gene 88 (MyD88) and IL-1 receptor 1 (IL-1R1) knockdown HNSCC cell lines, an IL-1R antagonist (IL-1RA), neutralizing antibodies to IL-1α and IL-1β, and recombinant IL-1α and IL-1β were used to determine cytokine production (using ELISA) in response to cetuximab in vitro. IL-1 pathway modulation in mouse models was accomplished by administration of IL-1RA, stable overexpression of IL-1α in SQ20B cells, administration of rIL-1α, and administration of a polyanhydride nanoparticle formulation of IL-1α. CD4+ and CD8+ T cell-depleting antibodies were used to understand the contribution of T cell-dependent anti-tumor immune responses. Baseline serum levels of IL-1α were measured using ELISA from HNSCC patients treated with cetuximab-based therapy and analyzed for association with progression free survival (PFS). Results: Cetuximab induced pro-inflammatory cytokine secretion from HNSCC cells in vitro which was mediated by an IL-1α/IL-1R1/MyD88-dependent signaling pathway. IL-1 signaling blockade did not affect the anti-tumor efficacy of cetuximab, while increased IL-1α expression using polyanhydride nanoparticles in combination with cetuximab safely and effectively induced a T cell-dependent anti-tumor immune response. Detectable baseline serum levels of IL-1α were associated with a favorable PFS in cetuximab-based therapy-treated HNSCC patients compared to HNSCC patients with undetectable levels. Conclusions: Altogether, these results suggest that IL-1α in combination with cetuximab can induce a T cell-dependent anti-tumor immune response and may represent a novel immunotherapeutic strategy for EGFR-positive HNSCCs.

Original languageEnglish (US)
Pages (from-to)1-16
Number of pages16
JournalJournal for ImmunoTherapy of Cancer
Volume7
Issue number1
DOIs
StatePublished - Mar 19 2019

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Interleukin-1alpha
Interleukin-1
Neoplasms
Epidermal Growth Factor Receptor
Polyanhydrides
T-Lymphocytes
Carcinoma, squamous cell of head and neck
Cetuximab
Interleukin-1 Receptors
Nanoparticles
Disease-Free Survival
Enzyme-Linked Immunosorbent Assay
Cytokines
Survival
Therapeutics

Keywords

  • Anakinra
  • Biomarker
  • Cetuximab
  • Cytokines
  • EGFR
  • HNSCC
  • Interleukin-1
  • Nanoparticle

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Espinosa-Cotton, M., Rodman, S. N., Ross, K. A., Jensen, I. J., Sangodeyi-Miller, K., McLaren, A. J., ... Simons, A. L. (2019). Interleukin-1 alpha increases anti-tumor efficacy of cetuximab in head and neck squamous cell carcinoma. Journal for ImmunoTherapy of Cancer, 7(1), 1-16. https://doi.org/10.1186/s40425-019-0550-z

Interleukin-1 alpha increases anti-tumor efficacy of cetuximab in head and neck squamous cell carcinoma. / Espinosa-Cotton, Madelyn; Rodman, Samuel N.; Ross, Kathleen A.; Jensen, Isaac J.; Sangodeyi-Miller, Kenley; McLaren, Ayana J.; Dahl, Rachel A.; Gibson-Corley, Katherine N.; Koch, Adam T.; Fu, Yang-Xin; Badovinac, Vladimir P.; Laux, Douglas; Narasimhan, Balaji; Simons, Andrean L.

In: Journal for ImmunoTherapy of Cancer, Vol. 7, No. 1, 19.03.2019, p. 1-16.

Research output: Contribution to journalArticle

Espinosa-Cotton, M, Rodman, SN, Ross, KA, Jensen, IJ, Sangodeyi-Miller, K, McLaren, AJ, Dahl, RA, Gibson-Corley, KN, Koch, AT, Fu, Y-X, Badovinac, VP, Laux, D, Narasimhan, B & Simons, AL 2019, 'Interleukin-1 alpha increases anti-tumor efficacy of cetuximab in head and neck squamous cell carcinoma', Journal for ImmunoTherapy of Cancer, vol. 7, no. 1, pp. 1-16. https://doi.org/10.1186/s40425-019-0550-z
Espinosa-Cotton, Madelyn ; Rodman, Samuel N. ; Ross, Kathleen A. ; Jensen, Isaac J. ; Sangodeyi-Miller, Kenley ; McLaren, Ayana J. ; Dahl, Rachel A. ; Gibson-Corley, Katherine N. ; Koch, Adam T. ; Fu, Yang-Xin ; Badovinac, Vladimir P. ; Laux, Douglas ; Narasimhan, Balaji ; Simons, Andrean L. / Interleukin-1 alpha increases anti-tumor efficacy of cetuximab in head and neck squamous cell carcinoma. In: Journal for ImmunoTherapy of Cancer. 2019 ; Vol. 7, No. 1. pp. 1-16.
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TY - JOUR

T1 - Interleukin-1 alpha increases anti-tumor efficacy of cetuximab in head and neck squamous cell carcinoma

AU - Espinosa-Cotton, Madelyn

AU - Rodman, Samuel N.

AU - Ross, Kathleen A.

AU - Jensen, Isaac J.

AU - Sangodeyi-Miller, Kenley

AU - McLaren, Ayana J.

AU - Dahl, Rachel A.

AU - Gibson-Corley, Katherine N.

AU - Koch, Adam T.

AU - Fu, Yang-Xin

AU - Badovinac, Vladimir P.

AU - Laux, Douglas

AU - Narasimhan, Balaji

AU - Simons, Andrean L.

PY - 2019/3/19

Y1 - 2019/3/19

N2 - Background: Despite the high prevalence of epidermal growth factor receptor (EGFR) overexpression in head and neck squamous cell carcinomas (HNSCCs), incorporation of the EGFR inhibitor cetuximab into the clinical management of HNSCC has not led to significant changes in long-term survival outcomes. Therefore, the identification of novel therapeutic approaches to enhance the clinical efficacy of cetuximab could lead to improved long-term survival for HNSCC patients. Our previous work suggests that EGFR inhibition activates the interleukin-1 (IL-1) pathway via tumor release of IL-1 alpha (IL-1α), although the clinical implications of activating this pathway are unclear in the context of cetuximab therapy. Given the role of IL-1 signaling in anti-tumor immune response, we hypothesized that increases in IL-1α levels would enhance tumor response to cetuximab. Methods: Parental and stable myeloid differentiation primary response gene 88 (MyD88) and IL-1 receptor 1 (IL-1R1) knockdown HNSCC cell lines, an IL-1R antagonist (IL-1RA), neutralizing antibodies to IL-1α and IL-1β, and recombinant IL-1α and IL-1β were used to determine cytokine production (using ELISA) in response to cetuximab in vitro. IL-1 pathway modulation in mouse models was accomplished by administration of IL-1RA, stable overexpression of IL-1α in SQ20B cells, administration of rIL-1α, and administration of a polyanhydride nanoparticle formulation of IL-1α. CD4+ and CD8+ T cell-depleting antibodies were used to understand the contribution of T cell-dependent anti-tumor immune responses. Baseline serum levels of IL-1α were measured using ELISA from HNSCC patients treated with cetuximab-based therapy and analyzed for association with progression free survival (PFS). Results: Cetuximab induced pro-inflammatory cytokine secretion from HNSCC cells in vitro which was mediated by an IL-1α/IL-1R1/MyD88-dependent signaling pathway. IL-1 signaling blockade did not affect the anti-tumor efficacy of cetuximab, while increased IL-1α expression using polyanhydride nanoparticles in combination with cetuximab safely and effectively induced a T cell-dependent anti-tumor immune response. Detectable baseline serum levels of IL-1α were associated with a favorable PFS in cetuximab-based therapy-treated HNSCC patients compared to HNSCC patients with undetectable levels. Conclusions: Altogether, these results suggest that IL-1α in combination with cetuximab can induce a T cell-dependent anti-tumor immune response and may represent a novel immunotherapeutic strategy for EGFR-positive HNSCCs.

AB - Background: Despite the high prevalence of epidermal growth factor receptor (EGFR) overexpression in head and neck squamous cell carcinomas (HNSCCs), incorporation of the EGFR inhibitor cetuximab into the clinical management of HNSCC has not led to significant changes in long-term survival outcomes. Therefore, the identification of novel therapeutic approaches to enhance the clinical efficacy of cetuximab could lead to improved long-term survival for HNSCC patients. Our previous work suggests that EGFR inhibition activates the interleukin-1 (IL-1) pathway via tumor release of IL-1 alpha (IL-1α), although the clinical implications of activating this pathway are unclear in the context of cetuximab therapy. Given the role of IL-1 signaling in anti-tumor immune response, we hypothesized that increases in IL-1α levels would enhance tumor response to cetuximab. Methods: Parental and stable myeloid differentiation primary response gene 88 (MyD88) and IL-1 receptor 1 (IL-1R1) knockdown HNSCC cell lines, an IL-1R antagonist (IL-1RA), neutralizing antibodies to IL-1α and IL-1β, and recombinant IL-1α and IL-1β were used to determine cytokine production (using ELISA) in response to cetuximab in vitro. IL-1 pathway modulation in mouse models was accomplished by administration of IL-1RA, stable overexpression of IL-1α in SQ20B cells, administration of rIL-1α, and administration of a polyanhydride nanoparticle formulation of IL-1α. CD4+ and CD8+ T cell-depleting antibodies were used to understand the contribution of T cell-dependent anti-tumor immune responses. Baseline serum levels of IL-1α were measured using ELISA from HNSCC patients treated with cetuximab-based therapy and analyzed for association with progression free survival (PFS). Results: Cetuximab induced pro-inflammatory cytokine secretion from HNSCC cells in vitro which was mediated by an IL-1α/IL-1R1/MyD88-dependent signaling pathway. IL-1 signaling blockade did not affect the anti-tumor efficacy of cetuximab, while increased IL-1α expression using polyanhydride nanoparticles in combination with cetuximab safely and effectively induced a T cell-dependent anti-tumor immune response. Detectable baseline serum levels of IL-1α were associated with a favorable PFS in cetuximab-based therapy-treated HNSCC patients compared to HNSCC patients with undetectable levels. Conclusions: Altogether, these results suggest that IL-1α in combination with cetuximab can induce a T cell-dependent anti-tumor immune response and may represent a novel immunotherapeutic strategy for EGFR-positive HNSCCs.

KW - Anakinra

KW - Biomarker

KW - Cetuximab

KW - Cytokines

KW - EGFR

KW - HNSCC

KW - Interleukin-1

KW - Nanoparticle

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