Head & neck · 2019
Immunogenomic correlates of response to cetuximab monotherapy in head and neck squamous cell carcinoma.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Faden Daniel L, Concha-Benavente Fernando, Chakka Anish B, McMichael Elizabeth L, Chandran Uma, Ferris Robert L
Аннотация
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.
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.
Предметные рубрики MeSH
AdultAgedAlkaloidsAntineoplastic Agents, ImmunologicalCarcinoma, Squamous CellCell Line, TumorCetuximabCohort StudiesFemaleHLA-A AntigensHLA-C AntigensHead and Neck NeoplasmsHistocompatibility Antigens Class IHumansInterferon-gammaKiller Cells, NaturalMaleMiddle AgedMutationReceptors, KIRReceptors, KIR3DL2Signal TransductionUp-RegulationExome Sequencing