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

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

doi:10.1186/s40425-019-0550-z

Abstract

BackgroundDespite 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.MethodsParental 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).ResultsCetuximab 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.ConclusionsAltogether, 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.

Highlights

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
Cetuximab induces secretion of pro-inflammatory cytokines To determine if cetuximab triggers proinflammatory cytokine release from HNSCC cells, Cal-27 and SQ20B cells were treated with 1, 10 and 100 μg/mL cetuximab for 48 h and cell culture media was analyzed for IL-1α, IL-6 and IL-8 by ELISA
Cell lines derived from myeloid differentiation primary response gene 88 (MyD88) stable knockout clones demonstrated significantly reduced IL-1α (Fig. 1D), IL-6 (Fig. 1E) and IL-8 (Fig. 1F) in the presence of cetuximab compared to control cells with the exception of IL-8 secretion from the shMyD88#2 clone at 10 and 100 μg/mL (Fig. 1F)

Summary

Introduction

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. The identification of novel therapeutic approaches to enhance the clinical efficacy of cetuximab could lead to improved long-term survival for HNSCC patients. The EGFR monoclonal IgG1 antibody cetuximab is the only FDA approved EGFR inhibitor for first-line treatment of R/M HNSCC. Immunotherapy with antibodies targeting programmed cell death protein-1 (PD-1) have shown great promise and are FDA approved for R/M HNSCC as second-line therapy. Single agent immunotherapy has only modest response rates (13–16%) yet these responses, in contrast to cetuximab-based therapy, are remarkably durable [7, 8]. The relatively high response rates of cetuximab-based therapy and the durable responses of immunotherapy provide a strong rationale for the development of novel EGFR-targeted/immunotherapy combination regimens

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