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Inhibition of EphB4-Ephrin-B2 Signaling Reprograms the Tumor Immune Microenvironment in Head and Neck Cancers.
Bhatia, Shilpa; Oweida, Ayman; Lennon, Shelby; Darragh, Laurel B; Milner, Dallin; Phan, Andy V; Mueller, Adam C; Van Court, Benjamin; Raben, David; Serkova, Natalie J; Wang, Xiao-Jing; Jimeno, Antonio; Clambey, Eric T; Pasquale, Elena B; Karam, Sana D.
Afiliação
  • Bhatia S; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
  • Oweida A; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
  • Lennon S; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
  • Darragh LB; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
  • Milner D; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
  • Phan AV; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
  • Mueller AC; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
  • Van Court B; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
  • Raben D; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
  • Serkova NJ; Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
  • Wang XJ; Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
  • Jimeno A; Veterans Affairs Medical Center, VA Eastern Colorado Health Care System, Aurora, Colorado.
  • Clambey ET; Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
  • Pasquale EB; Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
  • Karam SD; Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
Cancer Res ; 79(10): 2722-2735, 2019 05 15.
Article em En | MEDLINE | ID: mdl-30894369
Identifying targets present in the tumor microenvironment that contribute to immune evasion has become an important area of research. In this study, we identified EphB4-ephrin-B2 signaling as a regulator of both innate and adaptive components of the immune system. EphB4 belongs to receptor tyrosine kinase family that interacts with ephrin-B2 ligand at sites of cell-cell contact, resulting in bidirectional signaling. We found that EphB4-ephrin-B2 inhibition alone or in combination with radiation (RT) reduced intratumoral regulatory T cells (Tregs) and increased activation of both CD8+ and CD4+Foxp3- T cells compared with the control group in an orthotopic head and neck squamous cell carcinoma (HNSCC) model. We also compared the effect of EphB4-ephrin-B2 inhibition combined with RT with combined anti-PDL1 and RT and observed similar tumor growth suppression, particularly at early time-points. A patient-derived xenograft model showed reduction of tumor-associated M2 macrophages and favored polarization towards an antitumoral M1 phenotype following EphB4-ephrin-B2 inhibition with RT. In vitro, EphB4 signaling inhibition decreased Ki67-expressing Tregs and Treg activation compared with the control group. Overall, our study is the first to implicate the role of EphB4-ephrin-B2 in tumor immune response. Moreover, our findings suggest that EphB4-ephrin-B2 inhibition combined with RT represents a potential alternative for patients with HNSCC and could be particularly beneficial for patients who are ineligible to receive or cannot tolerate anti-PDL1 therapy. SIGNIFICANCE: These findings present EphB4-ephrin-B2 inhibition as an alternative to anti-PDL1 therapeutics that can be used in combination with radiation to induce an effective antitumor immune response in patients with HNSCC.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Receptor EphB4 / Efrina-B2 / Microambiente Tumoral / Carcinoma de Células Escamosas de Cabeça e Pescoço / Neoplasias de Cabeça e Pescoço Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Cancer Res Ano de publicação: 2019 Tipo de documento: Article País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Receptor EphB4 / Efrina-B2 / Microambiente Tumoral / Carcinoma de Células Escamosas de Cabeça e Pescoço / Neoplasias de Cabeça e Pescoço Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Cancer Res Ano de publicação: 2019 Tipo de documento: Article País de publicação: Estados Unidos