Fusobacterium nucleatum induces MDSCs enrichment via activation the NLRP3 inflammosome in ESCC cells, leading to cisplatin resistance

Abstract

Background To analyse the regulatory effect of Fusobacterium nucleatum (Fn) on NOD-like receptor protein 3 (NLRP3) and myeloid-derived suppressor cells (MDSCs) in oesophageal squamous cell carcinoma (ESCC) as well as its effect on cisplatin (CDDP) therapy and to explore its clinical significance. Methods Fn infection, NLRP3 expression and MDSCs infiltration in ESCC tissues were detected by RNAscope and immunohistochemistry (IHC). The correlation between these three factors and the clinicopathological features and survival of ESCC patients was analysed. A coculture system of human peripheral blood monocytes (PBMCs) and ESCC cells was established to simulate the tumour microenvironment. In vitro and in vivo models were used to analyse the effects of Fn on the percentage of MDSCs in the coculture system and the NLRP3 expression level and CDDP sensitivity of ESCC cells. Results Fn infection was consistent with high NLRP3 expression and MDSCs enrichment in ESCC tissues. Moreover, the survival time of ESCC patients was significantly shortened under Fn infection, high NLRP3 expression and MDSCs enrichment. In the in vitro and in vivo models, Fn induced abundant enrichment of MDSCs by inducing high expression of NLRP3 in ESCC cells and reducing the sensitivity of ESCC cells to CDDP. Conclusions Fn infection can induce high expression of NLRP3 in ESCC, lead to MDSCs enrichment, weaken the body's antitumour immunity, and lead to CDDP treatment resistance. The effective elimination of Fn and the inhibition of MDSCs enrichment may provide new strategies and treatments for ESCC. Highlights The survival of ESCC patients with Fn infection, high NLRP3 expression and MDSCs enrichment was significantly shortened. Fn infection could cause CDDP resistance in ESCC. Fn could induce the enrichment of MDSCs in the tumour microenvironment by activating NLRP3 in ESCC cells.

Fusobacterium nucleatum promotes esophageal squamous cell carcinoma progression and chemoresistance by enhancing the secretion of chemotherapy-induced senescence-associated secretory phenotype via activation of DNA damage response pathway

“… 22 Liang et al demonstrated recently that F. nucleatum increased the expression of NLRP3 followed by the enrichment of myeloid-derived suppressor cells, thereby leading to ESCC cell chemoresistance. 38 However, the underlying relationship between F. nucleatum and therapy-induced senescent ESCC cells to date remains unknown. In the present study, we observed that CDDP-induced senescent cells after co-cultured with F. nucleatum further exacerbated the SASP-driven ESCC cell proliferation, migration, invasion, and chemoresistance both in vitro and in vivo , suggesting the contribution of F. nucleatum to the secretion of the SASP by senescent cells.…”

The role of microbiota in esophageal squamous cell carcinoma: A review of the literature

“…50 Higher intratumoral F. nucleatum levels were related to lower chemotherapy response 60,63,64 and shortened survival in ESCC patients. 60 Based on the above literature, the abundance of P. gingivalis or F. nucleatum in the oral cavity and esophagus…”

“…In a cell‐line study, Nomoto et al demonstrated that F. nucleatum promotes ESCC cell growth and migration by activating the NOD1/RIPK2/NF‐κB pathway 59 . Liang et al revealed F. nucleatum induces immunosuppressive myeloid‐derived suppressor cell (MDSC) enrichment via activation of the NOD‐like receptor protein 3 (NLRP3) inflammasome 60–62 . F. nucleatum can also induce chemoresistance in ESCC cells by modulating autophagy 63 .…”

"Open Sesame" to the complexity of pattern recognition receptors of myeloid-derived suppressor cells in cancer

“…MDSCs exhibit an increased activation of NLRP3 during tumor development. Ablation of the NLRP3/pro-IL-1b inflammasome rewires MDSC function, promotes melanoma (112) and breast cancer (113) regression, and causes cisplatin resistance (114). NLRP3 inhibition and anti-PD-1 treatment significantly increased the antitumor efficacy of monotherapy by limiting MDSC-mediated T cell suppression and melanoma tumor progression (76).…”