Abstract
BackgroundEGFR-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.MethodsAn 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.ResultsDespite 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.ConclusionsTargeting TGF-β and prostaglandin E2 may allow for improved outcomes for cancer patients treated with combination immunotherapy and EGFR inhibitors.
Highlights
Epidermal growth factor receptor (EGFR)-targeted therapy is an attractive option for head and neck squamous cell carcinoma patients
We discovered that EGFR inhibition increased MHC-II expression, paradoxically it attenuated Helper T cell (HTL) responses against some head and neck squamous cell carcinoma (HNSCC) cells
Downregulation of EGFR-reactive CD4+ T cell responses against HNSCC cells pretreated with EGFR inhibitor Recently, we reported that the newly identified CD4+ T cell peptide epitope EGFR875–889 functions as a promiscuous MHC-II HTL epitope that can elicit effective antitumor responses towards tumors expressing various HER family member proteins that have a high degree of homology in the peptide sequence [8]
Summary
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. Amongst various types of immunotherapy, the induction of anti-tumor CD8 cytotoxic T lymphocyte (CTL) responses via vaccination with peptide epitopes has been widely applied in the clinical setting [1]. Many strategies have been applied to enhance antigenspecific anti-tumor immunity, including the activation of natural killer (NK) cells, conversion of macrophage phenotype, and immune-modulating adjuvants [2,3,4]. CD4+ helper T lymphocytes (HTLs) play a critical role in anti-cancer immunity by promoting the induction and survival of CD8+ CTLs. In addition, in some instances HTLs can exhibit direct anti-tumor cytotoxic activity. Longpeptide vaccines have been used with the purpose of inducing both CTL and HTL anti-tumor responses, with promising clinical results [7]
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