Gastric cancer mesenchymal stem cells inhibit natural killer cell function by up-regulating FBP1

Abstract

Introduction:The dysfunction of natural killer (nK) cells has been widely reported in malignancies, including in solid tumours. gastric cancer mesenchymal stem cells (gCMSCs) are one of the vital elements of stromal cells in the tumour environment (TME) which possess immunosuppressive activity. This study aimed to determine whether gCMSCs are involved in the inhibition of nK cell immune function and explore its underlying mechanism. Material and methods: CD107a and perforin expression of gCMSCs conditioned medium (gCMSCs-CM)-primed nK cells were detected by flow cytometry. To determine nK cell cytotoxicity, the CytoTox96 non-Radioactive Cytotoxicity assay kit was used. glucose uptake and lactate production assay were performed to evaluate the metabolism state of nK cells treated with gCMSCs-CM. The expression of FBP1 in nK cells was analysed by immunoblotting.Results: gCMSCs inhibited the degranulation capacity, perforin production and cytotoxicity of nK cells. gCMSCs-CM restrained nK cell glucose uptake and lactate production, thus weakening their glycolytic metabolism. FBP1 expression of nK cells was upregulated in the presence of gCMSCs-CM. using FBP1 inhibitor could reverse the dysfunctional state of nK cells.Conclusions: This study indicated that gCMSCs could exert immunosuppressive effects on nK cells by up-regulating FBP1 expression, opening up new avenues for nK cell-based gC immunotherapy.

Unravelling diagnostic clusters and immune landscapes of disulfidptosis patterns in gastric cancer through bioinformatic assay

“…We noticed that cluster A was highly correlated with abundant immune cell infiltration of natural killer cell, which has close connection with GC ( Figure 7C ). Natural killer (NK) cells as robust prognostic biomarkers, play a crucial regulatory role in preserving immunological homeostasis [ 29 ] and opening up new avenues for natural killer cell-based GC immunotherapy is beneficial for preventing the development of GC [ 30 ]. IL6 and IL33 were closely associated with natural killer cell.…”

Mesenchymal stem/stromal cells- a principal element for tumour microenvironment heterogeneity

“…MSCs from head and neck squamous cell cancer inhibit the proliferation of CD4 + and CD8 + T cells through indoleamine 2,3 dioxygenase activity ( 34 ). GCMSCs inhibit the degranulation ability, perforin production, and cytotoxicity of NK cells by up-regulating the expression of fructose-bisphosphatase 1 ( 95 ). Moreover, Lung cancer-associated MSCs reduce NK cells cytotoxicity by expressing IL-6 and prostaglandin E2 ( 96 ).…”

Tumor microenvironment-mediated immune tolerance in development and treatment of gastric cancer

“…In GC, the CD155T/TIGIT signaling pathway can inhibit the uptake of glucose by CD8 + T cells, thereby inhibiting its function ( 80 ). MSC can inhibit the glucose uptake and lactate production of NK cells by upregulating FBP1, thereby weakening their glycolytic metabolism and inhibiting the degranulation ability, perforin production, and cytotoxicity of NK cells ( 81 ). In GC, inhibition of Glycogen synthase kinase-3beta (GSK-3β) can increase the infiltration of CD8 + T memory stem cells (Tscm) in GC tissue, and promote their differentiation potential and anti-GC ability ( 82 ).…”