title: STAT1-Induced HLA Class I Upregulation Enhances Immunogenicity and Clinical Response to Anti-EGFR mAb Cetuximab Therapy in HNC Patients.
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.
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Raghvendra M
authors.initials: RM
authors.lastname: Srivastava
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Sumita
authors.initials: S
authors.lastname: Trivedi
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Fernando
authors.initials: F
authors.lastname: Concha-Benavente
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Jie
authors.initials: J
authors.lastname: Hyun-Bae
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Raja R
authors.initials: RR
authors.lastname: Seethala
authors.affiliation: Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Branstetter
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. ferrisrl@upmc.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D056747:Immunomodulation; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D066246:ErbB Receptors; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D000068818:Cetuximab