Clinical Significance of Fusobacterium nucleatum Infection and Regulatory T Cell Enrichment in Esophageal Squamous Cell Carcinoma

Abstract

A variety of pathogenic microorganisms promote tumor occurrence and development through long-term colonization in the body. Fusobacterium nucleatum (F. nucleatum) is abundant in precancerous esophageal lesions and is closely related to the malignant progression of esophageal squamous cell carcinoma (ESCC). The invasion of exogenous microorganisms can reshape the immune microenvironment, make the immune system incapacitated, and assist tumor cells in immune escape. A variety of pathogenic microorganisms induce the recruitment of regulatory T cell (Tregs) to allow tumor cells to escape immune surveillance and provide favorable conditions for their own long-term colonization. Tregs are one of the major obstacles to tumor immunotherapy and have a significant positive correlation with the occurrence and development of many kinds of tumors. Because F. nucleatum can instantly enter cells and colonize for a long time, we speculated that F. nucleatum infection could facilitate the immune escape of tumor cells through enrichment of Tregs and promote the malignant progression of ESCC. In this study, we found a significant concordance between F. nucleatum infection and Tregs infiltration. Therefore, we propose the view that chronic infection of F. nucleatum may provide favorable conditions for long-term colonization of itself by recruiting Tregs and suppressing the immune response. At the same time, the massive enrichment of Treg may also weaken the immune response and assist in the long-term colonization of F. nucleatum. We analyzed the correlation between F. nucleatum infection with the clinicopathological characteristics and survival prognosis of the patients. F. nucleatum infection was found to be closely related to sex, smoking, drinking, degree of differentiation, depth of invasion, lymph node metastasis, and clinical stage. The degree of differentiation, depth of infiltration, lymph node metastasis, clinical stage, and F. nucleatum infection are independent risk factors affecting ESCC prognosis. Additionally, the survival rate and median survival time were significantly shortened in the F. nucleatum infection positive group. Therefore, we propose that long-term smoking and alcohol consumption cause poor oral and esophageal environments, thereby significantly increasing the risk of F. nucleatum infection. In turn, F. nucleatum infection and colonization may weaken the antitumor immune response through Treg enrichment and further assist in self-colonization, promoting the malignant progression of ESCC.

Tumour microbiota structure predicts hypopharyngeal carcinoma recurrence and metastasis

“…Intratumor microbiota can affect tumour progression and metastasis through inducing DNA damage and driving oncogenic pathways [ 27 ], which are associated with poor prognosis. Microbiota in tumour can also generate an immune suppressive microenvironment by recruiting immunosuppressive cells, leading to tumour immune escape [ 29 , 30 ]. For example, Streptococcus gallolyticus can inhibit T cells by recruiting myeloid-derived suppressor cells (MDSCs), tumour-associated macrophages (TAMs) and dendritic cells (DCs) [ 31 ].…”

Clinical impact of Fn-induced high expression of KIR2DL1 in CD8 T lymphocytes in oesophageal squamous cell carcinoma

“…Our previous study confirmed that immunosuppressive regulatory T (Treg) cells were enriched in Fn-infected ESCC tissues. Moreover, a high abundance of Treg cells can cause antitumour immune inactivation [ 3 ]. These results suggest that Fn-mediated remodelling of the tumour immune microenvironment may promote the development of ESCC.…”

“…The sections were restained with haematoxylin (Solarbio), dehydrated with ethanol, cleared with xylene, and sealed with neutral gum. Refer to the manufacturer’s instructions and literature for the specific experimental steps [ 3 ]. The colocalization of CD8 and KIR2DL1 expression in two serial sections were observed by randomly selecting 5 (400×) fields of view with an optical microscope (Nikon).…”

“…Fusobacterium nucleatum (Fn) is an opportunistic oral pathogen [ 2 ]. Recent studies have indicated that Fn is intimately related to the development of ESCC [ 3 , 4 ]. Long-term colonization with Fn can not only enhance the proliferation and invasion abilities of cancer cells but also remodel the tumour microenvironment and inhibit the immune response [ 5 , 6 ].…”

Involvement of Fusobacterium nucleatum in malignancies except for colorectal cancer: A literature review

“…The top-ranked KEGG pathway in F. nucleatum -positive esophageal cancer was the “cytokine–cytokine receptor interaction”, thereby supporting the possible mechanism that F. nucleatum might contribute to the aggressive tumor behavior through the activation of chemokines, such as CCL20 ( 47 ). The infection and colonization of F. nucleatum might also facilitate the immune escape of tumor cells and weaken the antitumor immune response through enriching Treg cells, assisting the long-term self-colonization, and promoting the malignant progression of ESCC ( 50 ). In addition, 13 samples of F. nucleatum -positive ESCC were analyzed by the whole-exome sequencing and the results showed that the function of the mutant gene was mainly concentrated in the pathways regulating apoptosis and the epidermal growth factor-like protein domain ( 49 ).…”