Abstract
BackgroundImmune checkpoint inhibitors (ICIs), primarily anti-PD-1, are currently used to treat patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). However, only a minority of patients benefit from these costly therapies. Therefore, there is an unmet need to better understand the effect of ICIs on immune effector cells. This study aimed to investigate the effect of a PD-1 antibody and an IDO1 inhibitor on different lymphocyte populations (NK, CD4+, and CD8+ T cells) in term of migration, cytotoxicity, and cytokine release in the presence of HNSCC cells.MethodsUsing a microfluidic chip, we injected HSC-3 cells (an oral tongue squamous cell carcinoma cell line) embedded in a human tumor-derived matrix “myogel/fibrin” together with NK, CD4+, and CD8+ T cells in separate channels. The two channels were connected with microchannels. The PD-1 antibody nivolumab and IDO1 inhibitor epacadostat were added to the microfluidic chips. Lymphocyte migration and cytotoxicity were examined under fluorescent microscopy and cytokine release was measured using a FirePlex Human Discovery Cytokines Immunoassay.ResultsEpacadostat significantly increased the migration and infiltration of NK and CD4+ T cells, but not CD8+ T cells, towards the cancer cells. Nivolumab did not exhibit a similar effect. While CD8+ T cells alone showed near to no migration, adding CD4+ T cells enhanced migration towards the cancer cells. There was a mild nonsignificant increase in apoptosis of HSC-3 cells after adding epacadostat to lymphocytes. In contrast, HSC-3 proliferation was not affected by lymphocytes regardless of ICIs. Nivolumab significantly increased release of MIP1-α, IL-6, and IL-8 from NK, CD4+, and CD8+ T cells, respectively.ConclusionsThis study revealed that each subpopulation of lymphocytes respond differently to ICIs. We also revealed the subpopulation of lymphocytes responsible for the increases in specific serum cytokines after ICI treatment.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the eighth most common cancer worldwide and accounts for 3% of cancerrelated deaths [1, 2]
We previously reported that an IDO1 inhibitor enhances migration of PBMNCs towards carcinoma cells using HSC-3 cell line and two patients derived cancer cells [15]
We observed a significant increase in macrophage inflammatory protein 1 alpha (MIP1-a) levels for natural killer (NK) cells after nivolumab treatment, but this was not significant
Summary
Head and neck squamous cell carcinoma (HNSCC) is the eighth most common cancer worldwide and accounts for 3% of cancerrelated deaths [1, 2]. The incidence of HNSCC arising from the tongue and oropharynx has increased approximately 30% in the last 30 years [2]. The increase in oropharyngeal squamous cell carcinoma incidence is related to the rise in human papillomavirus (HPV) infections; there is no known specific etiology for the growing incidence of HPV-negative tongue cancers [2, 3]. Primary treatment of HNSCC patients consists of surgery and (chemo-)radiotherapy either alone or in combination [6]. Immunotherapy is the newest treatment modality for recurrent or metastatic HNSCC [7, 8]. Immune checkpoint inhibitors (ICIs), primarily anti-PD-1, are currently used to treat patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). This study aimed to investigate the effect of a PD-1 antibody and an IDO1 inhibitor on different lymphocyte populations (NK, CD4+, and CD8+ T cells) in term of migration, cytotoxicity, and cytokine release in the presence of HNSCC cells
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