Streptococcus species as potential therapeutics for oropharyngeal squamous cell carcinoma

Project summary/Abstract Although different treatments such as chemoradiation and immune checkpoint inhibitors (ICI) are used to treat oropharyngeal squamous cell carcinoma (OSCC), the 5-year survival rate in advanced OSCC is around 40%. These treatment options are costly and induce side effects in many patients, therefore, treatments that are effective, affordable, and cause fewer short- and long-term therapy-related health problems are needed to increase the survival rate while improving the quality of life of these patients, especially in minority populations. Oral commensal non-pathogenic Streptococcus species such as Streptococcus salivarius (S. salivarius) and S. vestibularis are important to maintain oral health, in part by decreasing pro-inflammatory cytokines such as IL-6 and IL-8, known to be associated with cancer progression. Also, we have preliminary data, obtained by students in the lab, demonstrating that (i) S. salivarius cell-free supernatant induces oropharyngeal cancer cell death, (ii) intratumoral injection of S. salivarius decreased the growth of HPV+ oropharyngeal tumors, leading to increased intratumoral infiltration of T cells, and (iii) application of S. salivarius in the oral cavity induced the activation of CD8+ and natural killer cells in tongue tumor-bearing mice. Therefore, we hypothesize that S. salivarius will stimulate anti-tumor immune responses and/or modulate the microbiota to promote oropharyngeal tumor regression. Our interdisciplinary team with experience in immunology, microbiology, cancer biology and student mentoring will allow us to achieve our overall objective to identify the anti-cancer and immunomodulatory properties of Streptococcus species within the tumor microenvironment and train the next generation of scientists in cancer immunology. To test our hypothesis, we will develop the following specific aims: (1) Identify oral commensal Streptococcus species that affect oropharyngeal squamous cell carcinoma survival, proliferation and migration, (2) Identify anti-tumorigenic functions induced by oral commensal Streptococcus species in preclinical models for oropharyngeal cancer. The long-term goal of this project is to develop microbial therapeutics for OSCC to address the overarching need to identify affordable cancer treatments and improve the prognosis of OSCC patients while reducing patient morbidity. Importantly, students will be trained in the establishment of preclinical cancer models, mammalian and bacterial cell culture assays and immunological assays to develop the next generation of immune-oncology scientists.