Immune Modulation of Head and Neck Squamous Cell Carcinoma and the Tumor Microenvironment by Conventional Therapeutics

Abstract

Head and neck squamous cell carcinoma (HNSCC) accounts for more than 600,000 cases and 380,000 deaths annually worldwide. While human papilloma virus (HPV)-associated HNSCCs have better overall survival compared to HPV-negative HNSCC, loco-regional recurrence remains a significant cause of mortality and additional combinatorial strategies are needed to improve outcomes. The primary conventional therapies to treat HNSCC are surgery, radiation, and chemotherapies; however multiple other targeted systemic options are used and being tested including cetuximab, bevacizumab, mTOR inhibitors, and metformin. In 2016 the first checkpoint blockade immunotherapy was approved for recurrent or metastatic HNSCC refractory to platinum based chemotherapy. This immunotherapy approval confirmed the critical importance of the immune system and immuno-modulation in HNSCC pathogenesis, response to treatment, and disease control. However, while immuno-oncology agents are rapidly expanding, the role that the immune system plays in the mechanism of action and clinical efficacy of standard conventional therapies is likely underappreciated. In this article, we focus on how conventional and targeted therapies may directly modulate the immune system and the tumor microenvironment to better understand the effects and combinatorial potential of these therapies in the context and era of immunotherapy.

Immune-related gene signature for predicting the prognosis of head and neck squamous cell carcinoma

“…Specifically, an increased infiltration of immune cells and inflammatory cytokines has been recognized in the HPVpositive tumor microenvironment. This may aid better cancer clearance after irradiation [7]. Thus, HPV infection could improve the outcome of HNSCC patients.…”

“…For patients suffering recurrent metastatic diseases, the median overall survival (OS) is only 10 to 13 months in the first-line chemotherapy setting and 6 months in the setting of second-line [6]. Moreover, long-term toxicity and morbidity may be induced by the treatment [7]. As a consequence, exploring a novel and reliable signature for prognosis is critical.…”

“…Gene expression signatures for survival stratification in HNSCC patients have been proposed by various studies. Elements of the immune system, such as the tumor immune evading mechanism, are increasingly recognized crucial in HNSCC progression [7][8][9]. The programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PDL-1) complex is part of an important immunecheckpoint which is involved in antitumor activity [10].…”

Development and Radiation Response Assessment in A Novel Syngeneic Mouse Model of Tongue Cancer: 2D Culture, 3D Organoids and Orthotopic Allografts

“…Our in vivo orthotopic model could also serve as a valuable tool to examine the activity of novel immunotherapeutic strategies against this disease. While immune checkpoint inhibitors have recently received approval for clinical use in head and neck cancer patients [41], the optimal dose, schedule and sequence of combining checkpoint inhibitors with standard of care chemoradiation regimens is still unclear [42,43]. As such, several ongoing trials are investigating the combination of these immune-oncology agents with chemotherapy, radiation and targeted therapies [43].…”

“…While immune checkpoint inhibitors have recently received approval for clinical use in head and neck cancer patients [41], the optimal dose, schedule and sequence of combining checkpoint inhibitors with standard of care chemoradiation regimens is still unclear [42,43]. As such, several ongoing trials are investigating the combination of these immune-oncology agents with chemotherapy, radiation and targeted therapies [43]. Given the costs associated with large scale randomized trials, our model could be useful in the conduct of imaging-guided preclinical trials of these immunomodulatory agents with radiation.…”