Abstract:
:The goal of this study was to characterize the molecular mechanisms underlying cetuximab-mediated upregulation of HLA class I antigen-processing machinery components in head and neck cancer (HNC) cells and to determine the clinical significance of these changes in cetuximab-treated HNC patients. Flow cytometry, signaling studies, and chromatin immunoprecipitation (ChIP) assays were performed using HNC cells treated with cetuximab alone or with Fcγ receptor (FcγR)-bearing lymphocytes to establish the mechanism of EGFR-dependent regulation of HLA APM expression. A prospective phase II clinical trial of neoadjuvant cetuximab was used to correlate HLA class I expression with clinical response in HNC patients. EGFR blockade triggered STAT1 activation and HLA upregulation, in a src homology-containing protein (SHP)-2-dependent fashion, more prominently in HLA-B/C than in HLA-A alleles. EGFR signaling blockade also enhanced IFNγ receptor 1 (IFNAR) expression, augmenting induction of HLA class I and TAP1/2 expression by IFNγ, which was abrogated in STAT1(-/-) cells. Cetuximab enhanced HNC cell recognition by EGFR853-861-specific CTLs, and notably enhanced surface presentation of a non-EGFR peptide (MAGE-3271-279). HLA class I upregulation was significantly associated with clinical response in cetuximab-treated HNC patients. EGFR induces HLA downregulation through SHP-2/STAT1 suppression. Reversal of HLA class I downregulation was more prominent in clinical responders to cetuximab therapy, supporting an important role for adaptive immunity in cetuximab antitumor activity. Abrogating EGFR-induced immune escape mechanisms and restoring STAT1 signaling to reverse HLA downregulation using cetuximab should be combined with strategies to enhance adaptive cellular immunity.
journal_name
Cancer Immunol Resjournal_title
Cancer immunology researchauthors
Srivastava RM,Trivedi S,Concha-Benavente F,Hyun-Bae J,Wang L,Seethala RR,Branstetter BF 4th,Ferrone S,Ferris RLdoi
10.1158/2326-6066.CIR-15-0053subject
Has Abstractpub_date
2015-08-01 00:00:00pages
936-45issue
8eissn
2326-6066issn
2326-6074pii
2326-6066.CIR-15-0053journal_volume
3pub_type
杂志文章abstract::Despite HER2-targeted therapies improving the outcome of HER2+ breast cancer, many patients experience resistance and metastatic progression. Cancer stem cells (CSC) play a role in this resistance and progression, thus combining HER2 targeting with CSC inhibition could improve the management of HER2+ breast cancer. Th...
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journal_title:Cancer immunology research
pub_type: 杂志文章
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journal_title:Cancer immunology research
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journal_title:Cancer immunology research
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journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-15-0103-T
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journal_title:Cancer immunology research
pub_type: 临床试验,杂志文章
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更新日期:2015-05-01 00:00:00
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journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-14-0114
更新日期:2015-04-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-16-0125
更新日期:2017-03-01 00:00:00
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journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-17-0698
更新日期:2018-09-01 00:00:00
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journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-18-0022
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journal_title:Cancer immunology research
pub_type: 杂志文章
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journal_title:Cancer immunology research
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journal_title:Cancer immunology research
pub_type: 临床试验,杂志文章
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journal_title:Cancer immunology research
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journal_title:Cancer immunology research
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journal_title:Cancer immunology research
pub_type: 杂志文章,多中心研究
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journal_title:Cancer immunology research
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journal_title:Cancer immunology research
pub_type: 杂志文章
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