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Immunogenomic correlates of response to cetuximab monotherapy in head and neck squamous cell carcinoma.

ABSTRACT: 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.

SUBMITTER: Faden DL

PROVIDER: S-EPMC6625877 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Immunogenomic correlates of response to cetuximab monotherapy in head and neck squamous cell carcinoma.

Faden Daniel L DL Concha-Benavente Fernando F Chakka Anish B AB McMichael Elizabeth L EL Chandran Uma U Ferris Robert L RL

Head & neck 20190304 8

<h4>Background</h4>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.<h4>Methods</h4>HNSCC tumors (n = 20) from a prospective trial of neoadjuvant cetuximab monotherapy underwent whole-exome sequencing. Expression of killer-cell immunoglobulin-like rece ...[more]

PMID: 30828910

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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.

Dataset Information

Immunogenomic correlates of response to cetuximab monotherapy in head and neck squamous cell carcinoma.

Publications

Immunogenomic correlates of response to cetuximab monotherapy in head and neck squamous cell carcinoma.

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