title: Tumor-derived TGF-β and prostaglandin E2 attenuate anti-tumor immune responses in head and neck squamous cell carcinoma treated with EGFR inhibitor.
abstract: BACKGROUND
  EGFR-targeted therapy is an attractive option for head and neck squamous cell carcinoma patients. We have recently reported the use of EGFR inhibitors as an adjunct treatment to enhance HLA-DR expression in tumor cells to improve cancer immunotherapy. Nevertheless, we observed that EGFR inhibitors resulted in decreased anti-tumor responses, regardless of upregulation of HLA-DR expression on the tumor cell. In this study, we specifically investigated the mechanisms by which EGFR inhibition modulated anti-tumor responses.
  
  
  METHODS
  An EGFR inhibitor erlotinib was used to assess the modulation of anti-tumor responses by tumor antigen-specific helper T cells. We then examined whether administration of the EGFR inhibitor altered tumor cytokine profiles and expression of immune-related molecules on tumor cells.
  
  
  RESULTS
  Despite the augmented HLA-DR expression on a gingival cancer cell line by EGFR inhibition, anti-tumor responses of EGFR reactive helper T cell clones against tumor cells were decreased. EGFR inhibition did not change the expression of CD80, CD86, or PD-L1 on the tumor cells. Conversely, production of transforming growth factor beta (TGF-β) and prostaglandin E2 was increased by EGFR inhibition, indicating that these immunosuppressive molecules were involved in diminishing tumor recognition by T cells. Significantly, attenuation of HTL responses against tumors after EGFR inhibition was reversed by the addition of anti-TGF-β antibody or COX2 inhibitors.
  
  
  CONCLUSIONS
  Targeting TGF-β and prostaglandin E2 may allow for improved outcomes for cancer patients treated with combination immunotherapy and EGFR inhibitors.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kumai
authors.forename: Kensuke
authors.initials: K
authors.lastname: Oikawa
authors.forename: Naoko
authors.initials: N
authors.lastname: Aoki
authors.forename: Shoji
authors.initials: S
authors.lastname: Kimura
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Harabuchi
authors.forename: Esteban
authors.initials: E
authors.lastname: Celis
authors.forename: Hiroya
authors.initials: H
authors.lastname: Kobayashi
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000276:immunology*; D045744:Cell Line, Tumor; D015232:Dinoprostone / Q000502:physiology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use*; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D016212:Transforming Growth Factor beta; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D015232:Dinoprostone