Prognostic value of intratumoral Fusobacterium nucleatum and association with immune-related gene expression in oral squamous cell carcinoma patients

Abstract

Changes in the oral microbiome, particularly Fusobacterium nucleatum, are associated with oral squamous cell carcinoma (OSCC). F. nucleatum has been reported to modulate local immunity in cancers. We aimed to assess the association between intratumoral F. nucleatum and clinico-pathological features, relapse, and overall survival (OS) in two independent cohorts of patients with OSCC, and to explore the interplay with immune-related genes. We retrospectively analyzed tissue samples from a first cohort of 122 patients with head and neck squamous cell carcinoma, including 61 OSCC (cohort #1), and a second cohort of 90 additional OSCC (cohort #2). We then performed a sensitivity analysis on the merged cohort of OSCC patients (N = 151). F. nucleatum 16S rRNA gene sequences were quantified using real-time quantitative PCR. The presence of gram-negative bacteria and macrophages was confirmed by LPS and CD163 immunostainings, respectively. F. nucleatum positivity was associated with older age, less alcohol and combined alcohol plus tobacco consumption, and less frequent lymph node invasion. There was a trend for a lower recurrence rate in F. nucleatum-positive cases, with less metastatic relapses compared to F. nucleatum-negative tumors, and significantly longer OS, relapse-free and metastasis-free survival. F. nucleatum status was independently associated with OS in multivariate analysis. Immune-related gene and immunohistochemistry analyses showed that gram-negative bacteria load inversely correlated with M2 macrophages. F. nucleatum-associated OSCC has a specific immune microenvironment, is more frequent in older, non-drinking patients, and associated with a favorable prognosis.

Fusobacterium nucleatum and oral cancer: a critical review

“…Two recently published studies have examined the prognostic effect of F. nucleatum in oral/head and neck cancer, and the findings are summarised in Table 1 [ 66 , 67 ]. Neuzillet et al found that F. nucleatum was significantly associated with improved overall survival, relapse-free survival and metastasis-free survival in their merged OSCC cohort [ 66 ].…”

“…Two recently published studies have examined the prognostic effect of F. nucleatum in oral/head and neck cancer, and the findings are summarised in Table 1 [ 66 , 67 ]. Neuzillet et al found that F. nucleatum was significantly associated with improved overall survival, relapse-free survival and metastasis-free survival in their merged OSCC cohort [ 66 ]. Similarly Chen et al found that F. nucleatum enrichment in HNSCC tumour tissues was significantly associated with better cancer-specific survival and a lower rate of relapse [ 67 ].…”

The Key Differences between Human Papillomavirus-Positive and -Negative Head and Neck Cancers: Biological and Clinical Implications

“…The bacterial species included in Fusobacterium are significantly enriched in HNSCC tissues, causing increased expression of virulence factors in the oral microbiome [110]. Metaanalysis of patient samples also showed a higher abundance of Fusobacterium in HNSCC tumor samples compared to both adjacent normal tissues and tissues from healthy individuals (Table 1) [110,116,122,123]. Ironically, however, patients with F. nucleatum-positive HNSCC showed a favorable prognosis compared to F. nucleatum-negative HNSCC patients [124], while F. nucleatum in esophageal cancer is associated with aggressive disease and poor survival [117].…”

“…Ironically, however, patients with F. nucleatum-positive HNSCC showed a favorable prognosis compared to F. nucleatum-negative HNSCC patients [124], while F. nucleatum in esophageal cancer is associated with aggressive disease and poor survival [117]. This may be attributed to F. nucleatum-mediated modulation of local immunity via downregulation of TNFSF4 and PDGFRβ in fibroblasts, both of which are associated with poor prognosis of HNSCC patients [116]. Additionally, F. nucleatum was correlated to low tobacco and alcohol use, suggesting a role in the TME independent of the major risk factors of HNSCC.…”

Biochemical Mechanisms Associating Alcohol Use Disorders with Cancers

“…Additionally, ethanol and its metabolites and the imbalance in the microbiome populations may affect gut permeability, permitting the passage of bacterial metabolites and endotoxins to the general circulation and inducing inflammation both locally and in distant organs [ 15 ]. As a representative example, Fusobacterium nucleatum , a bacteria resident in the oral cavity, secretes immune modulators, virulence factors, and microRNAs linked to the initiation and progression of the oral cavity [ 16 , 17 ], esophagus [ 18 ], or colorectal [ 19 , 20 ] cancer. In biopsies from patients suffering from colorectal cancer, the expanded bacteria population significantly correlated with alcohol consumption [ 20 ].…”