We showed that IL-1 blockade using anakinra did not affect cetuximab binding to the Fc gamma-receptor III (FcRIII, CD16) on NK cells (Fig.?6a) however, anakinra suppressed NK cell activation induced by cetuximab (Fig.?6b) and Lycopodine NK cell degranulation (Fig.?6c) when cultured at a 1:1 effector to target ratio. patients to facilitate patient management and allow for treatment modification. The goal of this work is to assess the potential of activating interleukin-1 (IL-1) ligands (IL-1 alpha [IL-1], IL-1 beta [IL-1]) as predictive biomarkers of survival outcomes in HNSCC patients treated with cetuximab-based chemotherapy. Methods Baseline gene, serum and tumor expression of interleukin-1 (IL-1) ligands were analyzed from The Cancer Genome Atlas (TCGA) database or clinical trials of cetuximab-based therapies and interrogated for associations with Lycopodine clinical outcome data. Results High tumor gene expression of IL-1 was associated with a more favorable overall survival in cetuximab-treated HNSCC patients but not in non-cetuximab-treated patients. In HNSCC patients treated with cetuximab-based chemotherapy, higher gene and circulating levels of IL-1 and IL-1 were correlated with a more favorable progression free survival compared to patients with low or undetectable levels of IL-1 ligands. Conclusions These findings suggest that IL-1 ligands may function as predictive biomarkers for tumor response to cetuximab-based chemotherapy in HNSCC patients and warrants further investigation and validation in larger clinical studies. (4C6?weeks old) were purchased from Envigo Laboratories (Huntingdon, Cambridgeshire, United Kingdom). Mice were housed in a pathogen-free barrier room in the Animal Care Facility at the University of Iowa and handled using aseptic procedures. Mice were allowed at least 3?days to acclimate prior to beginning experimentation, and food and water were made freely available. SQ20B (1??106 cells/mouse) were inoculated into athymic nude mice by subcutaneous injection of 0.1?mL aliquots of saline containing cancer cells into the right flank using 26 gauge needles. In vivo drug administration Drug treatment commenced 3?days after tumor inoculation. Female SQ20B tumor-bearing athymic mice (and were found to be significantly increased in tumors (Fig.?1a,b (IL-1RA) was significantly decreased in tumor versus normal tumors (Fig.?1c, = 0.02). RNA-sequencing data for HNSCC tumors (and were significantly associated with worse survival compared to low gene levels (Fig.?2a,b, = 0.002 and 0.005, respectively). On the other hand, in patients who were treated with cetuximab-based therapy (and gene levels were not associated with worse survival (Fig.?2d,e, = 0.18 and 0.02, respectively). In fact, and appeared to be associated with a more favorable survival in cetuximab-based therapy-treated patients although only the differences in reached significance (Fig.?2e, = 0.02). There was no difference in survival outcomes for cetuximab- or non-cetuximab-treated patients on the basis of tumor expression (Fig.?2c,f, = 0.67 and 0.55, respectively). Analysis of corresponding patient characteristics and available clinicopathological data indicated no differences between the cetuximab-based therapy versus non-cetuximab-based therapy-treated patient cohorts on the basis of sex, age, HPV status, treatment with radiotherapy, or proportion of early/late stage cases (Table?1). However, of the HNSCC patients analyzed, cetuximab-based therapy was associated with a significantly higher likelihood of relapse and a less complete treatment responses compared to non-cetuximab-based therapy (Table ?(Table1).1). Overall, these findings prompted the further evaluation of and gene expression and their association with survival outcomes in cetuximab-based therapy-treated HNSCC patients. Open in a separate window Fig. 1 Expression of IL-1 ligands is elevated in head Lycopodine and neck tumor versus normal tissue. Gene expression of (a), (b), and (c) from tumor ((a), (b) and (c) tumor gene expression; and HNSCC patients treated with cetuximab based therapy (Cetuximab) (n?=?34 [d-f]) according to with high ((a), (b) Rabbit Polyclonal to TUT1 and (c) tumor gene expression Table 1 HNSCC Patient Characteristics value(Fig.?3a, FDR-adjusted trended higher in patients with long PFS but fell short of statistical significance (Fig.?3b, FDR-adjusted (a) and (b) in HNSCC patients treated with first-line cetuximab-based chemotherapy separated into long progression free survival (PFS) ( ?12?months, = 0.038, n?=?5) and IL-1 (Fig.?4b, = 0.037, = 0.27 and 0.128 respectively). However, a late divergence in the survival curves was observed for both IL-1 (6?month survival?=?38%.