Abstract

Extracellular Vesicles as Prognostic Markers in HNSCC in Response to Immunotherapy: From Bedside to Bench

My Mahoney, Associate Professor, Thomas Jefferson University

We recently demonstrated that the pro-proliferative and -survival stem cell marker desmoglein 2 (Dsg2) enhances squamous cell carcinoma (SCC) tumor development through small extracellular vesicles (sEVs) in an IL-8/miR-146a dependent mechanism. In head and neck SCC (HNSCC), a linear correlation between Dsg2 and IL-8 was detected by RNAseq of tumor tissues. Here, in a 4-week window of opportunity trial, human papillomaviruses (HPV)+ and HPV- HNSCC patients received 2 doses of the immune checkpoint inhibitor anti-PD1 mAb, Nivolumab. Patients were stratified according to pathologic treatment response as demonstrated by reduction in tumor size. EVs isolated from post treatment tumor culture supernatant by FACS analysis, confirmed the downregulation of immune checkpoint receptors in responders. Transcriptomic analysis of the tumor tissues showed downregulation of Dsg2 in response to treatment. ELISA analysis of plasma showed significantly lower levels of IL-8 in responders as compared to non-responders. Interestingly, higher level of IL-8 was mainly in the HPV+ non-responders. Among HPV+ patients, approximately 30% have high IL-8 and all were non-responders. Understanding non-response to immunotherapy in HPV positive cohort has been elusive and the discovery of an association with IL-8 in the periphery could speak to an active HPV viral influence that may overshadow the effects of PD-1 inhibition or other immune mechanisms. Further investigation into a resistance to immunotherapy and the potential for confounding systemic and local factors is necessary to further understand this observation.