Matrisomal genes in squamous cell carcinoma of head and neck influence tumor cell motility and response to cetuximab treatment.
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ABSTRACT:
SUBMITTER: Goh KY
PROVIDER: S-EPMC9017752 | biostudies-literature | 2022 Apr
REPOSITORIES: biostudies-literature
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Matrisomal genes in squamous cell carcinoma of head and neck influence tumor cell motility and response to cetuximab treatment.
Goh Kah Yee KY Lau Kah Weng KW Cheng Terence You De TY Tham Su Chin SC Lim Chwee Teck CT Iyer Narayanan Gopalakrishna NG Lim Su Bin SB Lim Darren Wan-Teck DW
Cancer communications (London, England) 20220302 4
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Project description:To show the relationship between antibody delivery and therapeutic efficacy in head and neck cancers, in this study we evaluated the pharmacokinetics and pharmacodynamics of epidermal growth factor receptor (EGFR)-targeted immunotherapy and radioimmunotherapy by quantitative positron emission tomography (PET) imaging.EGFR expression on UM-SCC-22B and SCC1 human head and neck squamous cell cancer (HNSCC) cells were determined by flow cytometry and immunostaining. Tumor delivery and distribution of cetuximab in tumor-bearing nude mice were evaluated with small animal PET using (64)Cu-DOTA-cetuximab. The in vitro toxicity of cetuximab to HNSCC cells was evaluated by MTT assay. The tumor-bearing mice were then treated with four doses of cetuximab at 10 mg/kg per dose, and tumor growth was evaluated by caliper measurement. FDG PET was done after the third dose of antibody administration to evaluate tumor response. Apoptosis and tumor cell proliferation after cetuximab treatment were analyzed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Ki-67 staining. Radioimmunotherapy was done with (90)Y-DOTA-cetuximab.EGFR expression on UM-SCC-22B cells is lower than that on SCC1 cells. However, the UM-SCC-22B tumors showed much higher (64)Cu-DOTA-cetuximab accumulation than the SCC1 tumors. Cetuximab-induced apoptosis in SCC1 tumors and tumor growth was significantly inhibited, whereas an agonistic effect of cetuximab on UM-SCC-22B tumor growth was observed. After cetuximab treatment, the SCC1 tumors showed decreased FDG uptake, and the UM-SCC-22B tumors had increased FDG uptake. UM-SCC-22B tumors are more responsive to (90)Y-DOTA-cetuximab treatment than SCC1 tumors, partially due to the high tumor accumulation of the injected antibody.Cetuximab has an agonistic effect on the growth of UM-SCC-22B tumors, indicating that tumor response to cetuximab treatment is not necessarily related to EGFR expression and antibody delivery efficiency, as determined by PET imaging. Although PET imaging with antibodies as tracers has limited function in patient screening, it can provide guidance for targeted therapy using antibodies as delivery vehicles.
| S-EPMC2848903 | biostudies-other
Project description: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.
| S-EPMC6425573 | biostudies-literature
Project description:Objective: In patients with head and neck squamous cell carcinoma (HNSCC), cetuximab [a monoclonal antibody targeting epidermal growth factor receptor (EGFR)] has been shown to improve overall survival when combined with radiotherapy in the locally advanced setting or with chemotherapy in first-line recurrent and/or metastatic (R/M) setting, respectively. While biomarkers of resistance to cetuximab have been identified in metastatic colorectal cancer, no biomarkers of efficacy have been identified in HNSCC. Here, we aimed to identify biomarkers of cetuximab sensitivity/resistance in HNSCC. Methods: HNSCC patients treated with cetuximab at the Curie Institute, for whom complete clinicopathological data and formalin-fixed paraffin-embedded (FFPE) tumor tissue collected before cetuximab treatment were available, were included. Immunohistochemistry analyses of PTEN and EGFR were performed to assess protein expression levels. PIK3CA and H/N/KRAS mutations were analyzed using high-resolution melting (HRM) and Sanger sequencing. We evaluated the predictive value of these alterations in terms of progression-free survival (PFS). Results: Hot spot activating PIK3CA and KRAS/HRAS mutations were associated with poor PFS among HNSCC patients treated with cetuximab in the first-line R/M setting, but not among HNSCC patients treated with cetuximab in combination with radiotherapy. Loss of PTEN protein expression had a negative predictive value among HNSCC patients treated with cetuximab and radiotherapy. High EGFR expression did not predict cetuximab sensitivity in our patient population. Conclusions: Hot spot activating PIK3CA and RAS mutations predicted cetuximab resistance among HNSCC patients in the first-line R/M setting, whereas loss of PTEN protein expression predicted resistance to cetuximab when combined to radiotherapy.
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Project description:BACKGROUND:Mechanisms of resistance to immune-modulating cancer treatments are poorly understood. Using a novel cohort of patients with head and neck squamous cell carcinoma (HNSCC), we investigated mechanisms of immune escape from epidermal growth factor receptor-specific monoclonal antibody (mAb) therapy. METHODS:HNSCC tumors (n = 20) from a prospective trial of neoadjuvant cetuximab monotherapy underwent whole-exome sequencing. Expression of killer-cell immunoglobulin-like receptor (KIR) and human leukocyte antigen-C (HLA-C) and the effect of KIR blockade were assessed in HNSCC cell lines. RESULTS:Nonresponders to cetuximab had an increased rate of mutations in HLA-C compared to responders and HNSCC tumors (n = 528) in The Cancer Genome Atlas (P < 0.00001). In vitro, cetuximab-activated natural killer (NK) cells induced upregulation of HLA-C on HNSCC cells (P < 0.01) via interferon gamma. Treatment of NK cells with the anti-KIR mAb lirilumab increased killing of HNSCC cells (P < 0.001). CONCLUSIONS:Alterations in HLA-C may provide a mechanism of immune evasion through disruption of NK activation.
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Project description:Quantitative (iTRAQ 4-plex) proteomic analysis of progressive head and neck cancers
2022-03-01 | PXD001438 | Pride
Project description:Cetuximab, an EGFR-blocking antibody, is currently approved for treatment of metastatic head and neck squamous cell carcinoma (HNSCC), but its response rate is limited. In addition to blocking EGFR-stimulated cell signaling, cetuximab can induce endocytosis of ASCT2, a glutamine transporter associated with EGFR in a complex, leading to glutathione biosynthesis inhibition and cellular sensitization to ROS. Pyruvate dehydrogenase kinase-1 (PDK1), a key mitochondrial enzyme overexpressed in cancer cells, redirects glucose metabolism from oxidative phosphorylation toward aerobic glycolysis. In this study, we tested the hypothesis that targeting PDK1 is a rational approach to synergize with cetuximab through ROS overproduction. We found that combination of PDK1 knockdown or inhibition by dichloroacetic acid (DCA) with ASCT2 knockdown or with cetuximab treatment induced ROS overproduction and apoptosis in HNSCC cells, and this effect was independent of effective inhibition of EGFR downstream pathways but could be lessened by N-acetyl cysteine, an anti-oxidative agent. In several cetuximab-resistant HNSCC xenograft models, DCA plus cetuximab induced marked tumor regression, whereas either agent alone failed to induce tumor regression. Our findings call for potentially novel clinical trials of combining cetuximab and DCA in patients with cetuximab-sensitive EGFR-overexpressing tumors and patients with cetuximab-resistant EGFR-overexpressing tumors.
| S-EPMC6795401 | biostudies-literature
Project description:ObjectivesWe previously reported inferior outcomes for locally advanced head and neck cancer treated with cetuximab (C225) versus cisplatin (CDDP). We now examine if this difference persists when accounting for HPV status and update outcomes on the entire cohort.Materials and methodsFrom 3/106 to 4/1/08, 174 locally advanced head and neck cancer patients received definitive treatment with RT and CDDP (n=125) or RT and C225 (n=49). Of these, 62 patients had tissue available for HPV analysis.ResultsThe median follow-up was 47 months. The 3-year loco-regional failure, disease-free survival, and overall survival for CDDP versus C225 were 5.7% versus 40.2% (P<0.0001), 85.1% versus 35.4% (P<0.0001), and 90.0% versus 56.6% (P<0.0001), respectively. In the subset with tissue, there was no difference in rates of HPV or p16 positivity between the 2 groups. In this subset, the 3-year loco-regional failure, disease-free survival, and overall survival for CDDP versus C225 were 5.3% versus 32.0% (P=0.01), 86.8% versus 43.2% (P=0.002), and 86.7% versus 76.9% (P=0.09), respectively. Multivariate analysis continued to show a benefit for CDDP.ConclusionsWith longer follow-up and the inclusion of HPV and p16 status for about one third of patients where tissue was available, we continued to find superior outcomes with concurrent CDDP versus C225.
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