Peripheral Cytokine Levels Differ by HPV Status and Change Treatment-Dependently in Patients with Head and Neck Squamous Cell Carcinoma.

Daphne Mytilineos,Simon Laban,Chrysanthi Tsamadou,Daniel Fürst,Joannis Mytilineos,Angelika Oster,Gunnar Völkel,Adrian Von Witzleben,Johannes Doescher,Hans A Kestler,Jasmin Ezić,Thomas K Hoffmann,Ramin Lotfi,Patrick J Schuler,Marie-Nicole Theodoraki,Cornelia Brunner

doi:10.3390/ijms21175990

Abstract

Cytokines and immune mediators play an important role in the communication between immune cells guiding their response to infectious diseases or cancer. In this study, a comprehensive longitudinal analysis of serum cytokines and immune mediators in head and neck squamous cell carcinoma (HNSCC) patients was performed. In a prospective, non-interventional, longitudinal study, blood samples from 22 HNSCC patients were taken at defined time points (TP) before, during, and every 3 months after completion of (chemo)radio)therapy (CRT/RT) until 12 months after treatment. Serum concentrations of 17 cytokines/immune mediators and High-Mobility-Group-Protein B1 (HMGB1) were measured by fluorescent bead array and ELISA. Concentrations of sFas were significantly elevated during and after CRT/RT, whereas perforin levels were significantly decreased after CRT/RT. Levels of MIP-1β and Granzyme B differed significantly during CRT/RT by HPV status. Increased HMGB1 levels were observed at recurrence, accompanied by high levels of IL-4 and IL-10. The sFas increase and simultaneous perforin decrease may indicate an impaired immune cell function during adjuvant radiotherapy. Increased levels of pro-inflammatory cytokines in HPV+ compared to HPV− patients seem to reflect the elevated immunogenicity of HPV-positive tumors. High levels of HMGB1 and anti-inflammatory cytokines at recurrence may be interpreted as a sign of immune evasion.

Highlights

Head and neck squamous cell carcinoma (HNSCC) is diagnosed in almost 900,000 cases worldwide resulting in approximately 450,000 cancer deaths per year [1]
To confirm our findings of human papillomaviruses (HPV)-status as a major determinant of the cytokine and immune mediator profile, we investigated HNSCC samples from the TCGA cohort and used RNA-Seq data for the measured cytokine panel within primary tumor samples
Our findings suggest treatment-associated changes in the concentration of a T-cell related cytokine and immune mediator panel primarily for Perforin and soluble Fas receptor (sFas) during radiotherapy potentially impairing immune cell functions

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) is diagnosed in almost 900,000 cases worldwide resulting in approximately 450,000 cancer deaths per year [1]. A subgroup of HNSCC, typically oropharyngeal squamous cell carcinoma, can be attributed to high-risk human papillomaviruses (HPV) [3,4]. In comparison to HPV-negative patients, patients with HPV-positive tumors have a better prognosis, regardless of the type of conventional curative treatment [5,6,7]. In HPV-positive tumors these immune infiltrates are generally denser than in HPV-negative tumors indicating a “hot” tumor immune microenvironment [8,9,10,11,12]. The presence of HPV-specific immune cells in the tumor microenvironment is associated with a good prognosis [13]. HPV-positive tumors are characterized by a pronounced immune response which results in high expression of interferon-gamma (IFN-γ) associated gene expression, the so-called IFN-γ signature [14]

Methods

Results

Conclusion