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

Xiang Yuan,Fuyou Zhou,Xurong Hou,Huaxu Li,Yingjian Ma,Zijun Lan,Jiangtao Sun,Guifang Li,Gaochao Hou,Yiwen Liu,Mingyang Ma,Jinyu Kong,Shegan Gao,Feng Ren

doi:10.1158/2326-6066.cir-18-0709

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.

Highlights

Between 15% and 20% of newly diagnosed cancers are likely related to infection [1, 2]
RNA sequencing (RNA-seq) reveals a gene signature associated with P. gingivalis infection
To identify the genes involved in the dynamic and heterogeneous immune responses that occur in response to infection in the esophageal squamous cell carcinoma (ESCC) microenvironment, we focused on the gene encoding B7-H4, an immune-checkpoint protein and drug target

Summary

Introduction

Between 15% and 20% of newly diagnosed cancers are likely related to infection [1, 2]. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/). Not be oncogenic, they compromise the overall health of the host and can result in an exacerbation of lymphocyte exhaustion and disruption in the immune surveillance required for clearing transformed cells within the site of infection. This cascade favors the development of oncogenic processes [3]. The mechanisms driving bacterial evasion of host defenses and infection-associated immunopathology remain unclear

Methods

Results

Conclusion