Indomethacin Treatment of Mice with Premalignant Oral Lesions Sustains Cytokine Production and Slows Progression to Cancer.

Sara D Johnson,M Rita I Young

doi:10.3389/fimmu.2016.00379

Abstract

Current treatment options for head and neck squamous cell carcinoma (HNSCC) patients are often ineffective due to tumor-localized and systemic immunosuppression. Using the 4-NQO mouse model of oral carcinogenesis, this study showed that premalignant oral lesion cells produce higher levels of the immune modulator, PGE2, compared to HNSCC cells. Inhibiting prostaglandin production of premalignant lesion cells with the pan-cyclooxygenase inhibitor indomethacin stimulated their induction of spleen cell cytokine production. In contrast, inhibiting HNSCC prostaglandin production did not stimulate their induction of spleen cell cytokine production. Treatment of mice bearing premalignant oral lesions with indomethacin slowed progression of premalignant oral lesions to HNSCC. Flow cytometric analysis of T cells in the regional lymph nodes of lesion-bearing mice receiving indomethacin treatment showed an increase in lymph node cellularity and in the absolute number of CD8+ T cells expressing IFN-γ compared to levels in lesion-bearing mice receiving diluent control treatment. The cytokine-stimulatory effect of indomethacin treatment was not localized to regional lymph nodes but was also seen in the spleen of mice with premalignant oral lesions. Together, these data suggest that inhibiting prostaglandin production at the premalignant lesion stage boosts immune capability and improves clinical outcomes.

Highlights

The 5-year survival rate for patients with head and neck squamous cell carcinoma (HNSCC) remains at ~50% [1]
To investigate how inhibiting PGE2 impacts on immune cell cytokine production in the premalignant oral lesion environment, spleen cells from healthy C57BL/6 mice were cultured with media conditioned by supernatants from indomethacin-treated premalignant lesion cells or HNSCC cells
To more clearly represent the impact of indomethacin treatment on cytokine skewing by premalignant lesion cells and HNSCC cells, and to control for the impact of indomethacin on spleen cell cytokine production in control conditions, levels of cytokines in these cultures were normalized to the levels produced by spleen cells in the presence of equal concentrations of indomethacin in media alone (Figure 1)

Summary

Introduction

The 5-year survival rate for patients with head and neck squamous cell carcinoma (HNSCC) remains at ~50% [1]. Traditional treatments for HNSCC patients, including surgical resection and chemoradiation, often fail due to the high incidence of cancer recurrence. There exists a critical need for more effective therapies, and there has been a recent interest in incorporating immunotherapies in the treatment plan for patients with HNSCC. The effectiveness of immunotherapy may be compromised by the pronounced immune inhibition in HNSCC patients [2,3,4]. Established HNSCC tumors use a variety of mechanisms to thwart the T cell-mediated antitumor response, including downregulation of MHC-II molecule expression, upregulation of death ligand expression (FasL) and direct secretion of several immunosuppressive molecules, including TGF-β and PGE2 [5, 6].

Methods

Results

Conclusion