Blockade of Immune-Checkpoint B7-H4 and Lysine Demethylase 5B in Esophageal Squamous Cell Carcinoma Confers Protective Immunity against P. gingivalis Infection

Abstract

Pathogens are capable of hijacking immune defense mechanisms, thereby creating a tolerogenic environment for hypermutated malignant cells that arise within the site of infection. Immune checkpoint-oriented immunotherapies have shown considerable promise. Equally important, the epigenetic reprogramming of an immune-evasive phenotype that activates the immune system in a synergistic manner can improve immunotherapy outcomes. These advances have led to combinations of epigenetic-and immune-based therapeutics. We previously demonstrated that Porphyromonas gingivalis isolated from esophageal squamous cell carcinoma (ESCC) lesions represents a major pathogen associated with this deadly disease. In this study, we examined the mechanisms associated with host immunity during P. gingivalis infection and demonstrated that experimentally infected ESCC responds by increasing the expression of B7-H4 and lysine demethylase 5B, which allowed subsequent in vivo analysis of the immunotherapeutic effects of anti-B7-H4 and histone demethylase inhibitors in models of chronic infection and immunity against xenografted human tumors. Using three different preclinical mouse models receiving combined therapy, we showed that mice mounted strong resistance against P. gingivalis infection and tumor challenge. This may have occurred via generation of a T cell-mediated response in the microenvironment and formation of immune memory. In ESCC subjects, coexpression of B7-H4 and KDM5B correlated more significantly with bacterial load than with the expression of either molecule alone. These results highlight the unique ability of P. gingivalis to evade immunity and define potential targets that can be exploited therapeutically to improve the control of P. gingivalis infection and the development of associated neoplasia.

Porphyromonas gingivalis and Its Systemic Impact: Current Status

“…Carcinogen metabolism by P. gingivalis may therefore be a possible mechanism [ 84 ]. Further, Yuan et al highlighted the ability of P. gingivalis to evade immune surveillance, and they determined that the blockade of immune-checkpoint B7-H4 and lysine demethylase 5b in ESCC conferred resistance against P. gingivalis infection and tumor challenge, proposing them as potential therapeutic targets for controlling P. gingivalis infection and its associated neoplasia [ 86 ]. Furthermore, P. gingivalis can enhance ESCC cell proliferation and metastasis by triggering the NF-κB signaling pathway [ 87 ] or via the miR-194/GRHL3/PTEN/Akt axis [ 88 ].…”

Neferine induces apoptosis by modulating the ROS‑mediated JNK pathway in esophageal squamous cell carcinoma

“…Currently, ESCC patients are mainly treated using surgical approaches, as well as by radiotherapy or chemotherapy, depending on the pathological results. Although chemotherapeutic drugs improve outcomes of esophageal carcinoma patients to a certain extent, the prognosis of ESCC remains dismal (2). Although several antitumor drugs such as paclitaxel (6), vincristine (8) and colchicine (31), are available for clinical application, they have limited efficacy in killing tumor cells.…”

“…Esophageal carcinoma (EC), that occurs in the squamous or glandular epithelium of the esophagus, represents the predominant type of gastrointestinal tumors (1,2). EC is further divided into esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (3).…”

“…In China, studies indicate that ~150,000 people succumb to EC every year, with >90% of them diagnosed with ESCC (4). Although some progress has been achieved with regard to diagnosis and treatment of ESCC, its five-year survival rate remains low (2). It is, therefore, imperative to develop antitumor drugs that effectively improve the overall survival rates, while conferring low toxicity to patients.…”

Role of the oral microbiota in cancer evolution and progression

“…93,118 A recent study suggested that blockade of immune checkpoints could effectively diminish the carcinogenic influence of P. gingivalis in ESCC. 119 F. nucleatum can also induce high-level expression of some pro-inflammatory cytokines including IL-6 and IL-8, 31 which are key promoters in inflammation-related diseases.…”