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

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.Electronic supplementary materialThe online version of this article (10.1186/s40425-019-0550-z) contains supplementary material, which is available to authorized users.

Simultaneous targeting tumor cells and cancer-associated fibroblasts with a Paclitaxel-Hyaluronan bioconjugate: in vitro evaluation in non-melanoma skin cancer

“…Augmented expression of IL6 in the peritumoural skin seems to be related to chronic UV-exposure rather than to the presence of neoplastic cells, since IL6 is almost absent within BCC [20]. IL-1α in combination with EGFR inhibitor can induce a T cell-dependent anti-tumor immune response in head and neck squamous cell carcinoma [106]. Acute in ammation, mainly extensive production of IL1β by CAFs signi cantly contributes to the e cacy of photodynamic therapy in cutaneous SCC [107].…”

Simultaneous Targeting Tumor Cells and Cancer-Associated Fibroblasts with a Paclitaxel-Hyaluronan Bioconjugate: in vitro Evaluation in Non-Melanoma Skin Cancer

“…Augmented expression of IL6 in the peritumoural skin seems to be related to chronic UVexposure rather than to the presence of neoplastic cells, since IL6 is almost absent within BCC [20]. IL-1α in combination with EGFR inhibitor can induce a T cell-dependent anti-tumor immune response in head and neck squamous cell carcinoma [104]. Acute in ammation, mainly extensive production of IL1b by CAFs signi cantly contributes to the e cacy of photodynamic therapy in cutaneous SCC [105].…”

Effects of in IL-1B/IL-1RN variants on the susceptibility to head and neck cancer in a chinese Han population

“…Overexpression of IL-1 activity increases the growth and metastasis of HNC [ 18 ]. IL1 was identified to be associated with the increased anti-tumor efficacy of cetuximab in HNC [ 19 ]. The intervention of IL-1β-CCL22-CCR4 signaling axis might provide a new treatment strategy for HNC [ 20 ].…”