Health-associated oral bacteria as anti-cancer and immunomodulatory agents in oral cancer

PROJECT SUMMARY
Oral squamous cell carcinoma (OSCC) exerts a significant clinical and financial burden worldwide. OSCC
continues to have poor prognosis despite advances in treatment modalities including surgery, radiotherapy and
immunotherapy, highlighting the urgent need for development of novel therapeutic strategies for this deadly
disease. Recently, there has been increasing interest in the role of the microbiome in OSCC. Extensive
research—including studies by Dr. Al-Hebshi—has shown OSCC to be associated with a distinct microbiome.
However, mechanistic in vitro and animal studies have almost exclusively focused on exploring of the role of
tumor-associated species (i.e. the pathobionts) while overlooking the potentially protective role health-associated
species could play in oral carcinogenesis. Indeed, there is growing evidence to support the use of natural and
engineered bacteria as anti-tumor agents. Additionally, studies have found the microbiome to modulate response
to cancer immunotherapy. However, such studies in the context of oral microbiome and oral cancer are lacking.
Our overarching goal is to identify oral bacterial species with anti-cancer properties and exploit them for
prevention or/and treatment of OSCC. Our central hypothesis, supported by preliminary data, is that health-
associated oral bacteria can interfere with OSCC tumor development and progression by inducing cytotoxicity
in cancer cells, inhibiting proliferation, downregulating CD36, and/or modulating the microbiome. We also
hypothesize that health-associated oral bacteria activate antitumor immunity, which in turn can enhance efficacy
of immunotherapy. To address these hypotheses, we propose the following Specific Aims: Aim 1 To assess
effect of S. mitis and H. parainfluenzae on development of chemically-induced OSCC in vivo (Prevention setting);
Aim 2 To study the ability of these species to modify the response of chemically-induced OSCC to checkpoint
inhibitor immunotherapy (Adjunctive therapy setting). We will employ a range of technologies including digital
imaging, histopathology, immunohistochemistry, flow cytometry, q-PCR, fluorescent in-situ hybridization and
16S and RNA sequencing to investigate the effect of treating 4-NQO mice with the test species. The proposed
studies explore for the first time the novel concept of using health-associated bacteria as anticancer and
immunomodulatory agents in OSCC. These studies have high potential for translational impact in OSCC.
Given the accessibility of the oral cavity, local delivery of bacterial species with anti-cancer properties via gel,
mouthwash, or lozenge may be used in human subjects as a new paradigm for OSCC prevention and/or as
adjunctive therapy. An additional strength of our approach is that it employs health-associated bacteria, that are
unlikely to be cleared by the immune system or to induce adverse effects.

Grant Number: 1R21DE033458-01A1
NIH Institute/Center: NIH
Principal Investigator: Nezar Al-Hebshi