Proton Treatment Suppresses Exosome Production in Head and Neck Squamous Cell Carcinoma

Abstract

Proton therapy (PT) is emerging as an effective and less toxic alternative to conventional X-ray-based photon therapy (XRT) for patients with advanced head and neck squamous cell carcinomas (HNSCCs) owing to its clustered dose deposition dosimetric characteristics. For optimal efficacy, cancer therapies, including PT, must elicit a robust anti-tumor response by effector and cytotoxic immune cells in the tumor microenvironment (TME). While tumor-derived exosomes contribute to immune cell suppression in the TME, information on the effects of PT on exosomes and anti-tumor immune responses in HNSCC is not known. In this study, we generated primary HNSCC cells from tumors resected from HNSCC patients, irradiated them with 5 Gy PT or XRT, and isolated exosomes from cell culture supernatants. HNSCC cells exposed to PT produced 75% fewer exosomes than XRT- and non-irradiated HNSCC cells. This effect persisted in proton-irradiated cells for up to five days. Furthermore, we observed that exosomes from proton-irradiated cells were identical in morphology and immunosuppressive effects (suppression of IFN-γ release by peripheral blood mononuclear cells) to those of photon-irradiated cells. Our results suggest that PT limits the suppressive effect of exosomes on cancer immune surveillance by reducing the production of exosomes that can inhibit immune cell function.

Current Status and Future Directions of Proton Therapy for Head and Neck Carcinoma

“…Multiple elements of the tumor microenvironment also contribute to mechanisms to evade immune surveillance, including small tumor-derived extracellular vesicles, also known as exosomes [ 63 , 64 ]. A recent in silico paper by Chimote et al on primary HNSCC cells irradiated with 5 Gy PT or X-ray RT reported that PT lead to the production of 75% fewer exosomes compared to X-ray RT and non-irradiated HNSCC cells [ 65 ]. The inhibition of exosome production could highlight the advantages of PT over photon-based RT in enhancing anti-tumor immunity, as well as the potential benefits of combining PT with immune checkpoint inhibitors and various other forms of immunotherapy.…”