4.7 Article

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

Journal

JOURNAL FOR IMMUNOTHERAPY OF CANCER
Volume 7, Issue -, Pages -

Publisher

BMC
DOI: 10.1186/s40425-019-0550-z

Keywords

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

Funding

  1. 2016 AACR-Bayer Innovation and Discovery Grant [16-80-44-SIMO]
  2. National Institutes of Health (NIH) [R01DE024550, F99CA223062]
  3. Department of Pathology Research Grant

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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-1 alpha), 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-1 alpha 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-1 alpha and IL-1 beta, and recombinant IL-1 alpha and IL-1 beta 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-1 alpha in SQ20B cells, administration of rIL-1 alpha, and administration of a polyanhydride nanoparticle formulation of IL-1 alpha. 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-1 alpha 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-1 alpha/IL-1R1/MyD88-dependent signaling pathway. IL-1 signaling blockade did not affect the anti-tumor efficacy of cetuximab, while increased IL-1 alpha 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-1 alpha 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-1 alpha 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.

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