Molecular and Functional Profiles of Exosomes From HPV(+) and HPV(-) Head and Neck Cancer Cell Lines.

Sonja Ludwig,Theresa L Whiteside,Soldano Ferrone,Monika Pietrowska,Marie-Nicole Theodoraki,Saigopalakrishna S Yerneni,Stephan Lang,Priyanka Sharma

doi:10.3389/fonc.2018.00445

Abstract

Exosomes produced by tumor cells have been shown to reprogram functions of human immune cells. Molecular cargos of exosomes isolated from supernatants of HPV(+) and HPV(−) head and neck cancer (HNC) cell lines or from HNC patients' plasma were compared. The exosome protein profiles resembled those of respective parent tumor cells. Only HPV(+) exosomes carried E6/E7, p16, and survivin. HPV(−) exosomes were negative for cyclin D1 and carried low p53 levels. Immunomodulatory molecules (TGF-β, FasL, OX40, OX40L, and HSP70) were carried by HPV(+) and HPV(−) exosomes. These exosomes co-incubated with human T cells induced apoptosis and suppressed T cell activation and proliferation. HPV(−) exosomes suppressed DC maturation and expression of antigen processing machinery (APM) components. In contrast, HPV(+) exosomes promoted DC maturation and did not suppress expression of APM components in mature DCs. While DCs readily internalized exosomes, T lymphocytes resisted their uptake during the initial 12 h co-culture. Thus, HPV(+) exosomes capable of sustaining DC functions may play a key role in promoting anti-tumor immune responses thereby improving outcome in patients with HPV(+) cancers.

Highlights

Persistent infection with human papillomavirus (HPV) type 16 is a major risk factor for the development of head and neck cancers (HNCs), especially oropharyngeal squamous cell carcinoma (OPSCC) [1, 2]
The rationale for this comparison was based on the premise that exosomes which originate from the endocytic compartment of the parent tumor cell carry proteins that simulate the molecular content and functions of the parent
Exosomes that mimic the parent cell could serve as surrogates of HPV(+) or HPV(−) tumor cells reflecting the effects these tumor-derived exosomes exert on tissue and immune cells

Summary

Introduction

Persistent infection with human papillomavirus (HPV) type 16 is a major risk factor for the development of head and neck cancers (HNCs), especially oropharyngeal squamous cell carcinoma (OPSCC) [1, 2]. The HPV(+) OPSCC has clinical, histopathological, and molecular characteristics that are different from those in HPV(−) HNCs [3]. HPV(+) OPSCCs occur in younger individuals without the history of smoking or alcohol abuse that is usually associated with HNC carcinogenesis [4]. HPV(+) HNCs respond better to therapy, have significantly better prognosis and significantly better outcome than HPV(−) HNCs [4]. Despite these differences in etiology and sensitivity to therapy, HPV(+) and HPV(−) HNCs are currently treated with the same therapeutic regimen, consisting of surgery followed by fractionated radiation, and chemotherapy [5].

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Results

Conclusion