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.

Microbial dysbiosis in the upper digestive tract is linked to an increased risk of esophageal squamous cell carcinoma (ESCC). Overabundance of Porphyromonas gingivalis is associated with shorter survival of ESCC patients. We investigated the molecular mechanisms driving aggressive progression of ESCC by P . gingivalis . Intracellular invasion of P . gingivalis potentiated proliferation, migration, invasion, and metastasis abilities of ESCC cells via transforming growth factor-β (TGFβ)-dependent Drosophila mothers against decapentaplegic homologs (Smads)/Yes-associated protein (YAP)/Transcriptional coactivator with PDZ-binding motif (TAZ) activation. Smads/YAP/TAZ/TEA domain transcription factor1 (TEAD1) complex formation was essential to initiate downstream target gene expression, inducing an epithelial–mesenchymal transition (EMT) and stemness features. Furthermore, P . gingivalis augmented secretion and bioactivity of TGFβ through glycoprotein A repetitions predominant (GARP) up-regulation. Accordingly, disruption of either the GARP/TGFβ axis or its activated Smads/YAP/TAZ complex abrogated the tumor-promoting role of P . gingivalis . P . gingivalis signature genes based on its activated effector molecules can efficiently distinguish ESCC patients into low- and high-risk groups. Targeting P . gingivalis or its activated effectors may provide novel insights into clinical management of ESCC.

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Mounting evidence suggests a causal relationship between specific bacterial infections and the development of certain malignancies. In this study, we examined the presence of Porphyromonas gingivalis (P. gingivalis) in oral-digestive tract tumors by immunohistochemistry (IHC) and PCR and analyzed the correlation between P. gingivalis detection and clinicopathological characteristics and prognosis of oral and esophageal carcinoma. The IHC results showed that the positive rates of P. gingivalis were 60.00, 46.00, 20.00, 6.67, and 2.86% in oral, esophagus, cardiac, stomach, and colorectal cancer tissues, respectively. Likewise, PCR results showed rates of 56.00, 42.00, 16.67, 3.33, and 2.86%, respectively. The two methods were consistent, and the kappa value was 0.806, P < 0.001. In addition, P. gingivalis expression was significantly correlated with lymph node metastasis and the clinical stages of oral and esophageal cancer (P < 0.05). The overall survival rate of the P. gingivalis undetected group (86, 50%) was significantly higher than that of the P. gingivalis detected group (57, 14%) for oral and esophageal cancer, respectively. In conclusion, the detection rate of P. gingivalis showed a decreasing trend in oral-digestive tract tumors. Detection with P. gingivalis was associated with poor prognosis for oral and esophageal cancer.

Background: The aim of this study was to identify prognostic markers for esophageal squamous cell carcinoma (ESCC) and build an effective prognostic nomogram for ESCC.Methods: A total of 365 patients with ESCC from three medical centers were divided into four cohorts. In the discovery phase of the study, we analyzed transcriptional data from 179 cancer tissue samples and identified nine marker genes using edgeR and rbsurv packages. In the training phase, penalized Cox regression was used to select the best marker genes and clinical characteristics in the 179 samples. In the verification phase, these marker genes and clinical characteristics were verified by internal validation cohort (n = 58) and two external cohorts (n = 81, n = 105).Results: We constructed and verified a nomogram model based on multiple clinicopathologic characteristics and gene expression of a patient cohort undergoing esophagectomy and adjuvant radiochemotherapy. The predictive accuracy for 4-year overall survival (OS) indicated by the C-index was 0.75 (95% CI, 0.72–0.78), which was statistically significantly higher than that of the American Joint Committee on Cancer (AJCC) seventh edition (0.65). Furthermore, we found two marker genes (TM9SF1, PDZK1IP) directly related to the OS of esophageal cancer.Conclusion: The nomogram presented in this study can accurately and impersonally predict the prognosis of ESCC patients after partial resection of the esophagus. More research is required to determine whether it can be applied to other patient populations. Moreover, we found two marker genes directly related to the prognosis of ESCC, which will provide a basis for future research.