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

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

  • Cancer Immunol Res. 2019 Sep;7(9):1440-1456. doi: 10.1158/2326-6066.CIR-18-0709.
Xiang Yuan 1 2,  Yiwen Liu 1,  Guifang Li 3,  Zijun Lan 1,  Mingyang Ma 3,  Huaxu Li 4,  Jinyu Kong 1,  Jiangtao Sun 3,  Gaochao Hou 1,  Xurong Hou 2,  Yingjian Ma 1,  Feng Ren 5,  Fuyou Zhou 6,  Shegan Gao 7 2
Affiliations

Affiliations

  • 1 Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China.
  • 2 Department of Medical Oncology, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China.
  • 3 Department of Pulmonary Tumor Surgery, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China.
  • 4 Queen Mary College, Medical College of Nanchang University, Nanchang, China.
  • 5 Department of Pathology, Xinxiang Medical University, Xinxiang, China.
  • 6 Department of Thoracic Surgery, Anyang Tumor Hospital, Anyang, Henan, China. gsgvicepresident@163.com ayzhoufuyou@163.com.
  • 7 Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China. gsgvicepresident@163.com ayzhoufuyou@163.com.
PMID: 31350278 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.

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