Abstract
BackgroundEndoplasmic reticulum (ER) stress has been found to foster the escape of cancer cells from immune surveillance and upregulate PD-L1 expression. However, the underlying mechanisms are unknown.MethodsWhile analyzing the protein levels using immunofluorescence and Western blotting, the RNA levels were measured using qRT-PCR. Ten injection of exosomes into six-week-old nude mice was made through the tail vein once every other day in total.ResultsThe expression of certain ER stress markers such as PERK (PKR-like endoplasmic reticulum kinase), ATF6 (activating transcription factor 6), and GRP78 (glucose-regulated protein 78), was found to be upregulated in the oral squamous cell carcinoma (OSCC) tissues and related to poor overall survival. There is a positive relationship between the extent of ER stress-related proteins and a cluster of PD-L1 expression and macrophage infiltration among the OSCC tissues. Further, incubation with exosomes derived from ER-stressed HN4 cells (Exo-ER) was found to upregulate PD-L1 extents in macrophages in vitro and in vivo, and macrophage polarization toward the M2 subtype was promoted by upregulating PD-L1.ConclusionsER stress causes OSCC cells to secrete exosomal PD-L1 and upregulates PD-L1 expression in macrophages to drive M2 macrophage polarization. The delineation of a new exosome-modulated mechanism was made for OSCC–macrophage crosstalk driving tumor development and to be examined for its therapeutic use.Graphical abstractExosomal PD-L1 secreted by ER-stressed OSCC cells promoted M2 macrophage polarization. BvoEQJGxSejnxUc-5MZRg5Video .
Highlights
Endoplasmic reticulum (ER) stress has been found to foster the escape of cancer cells from immune surveillance and upregulate Programmed cell death-ligand 1 (PD-L1) expression
Exosomal PD-L1 secreted by ER-stressed Oral squamous cell carcinoma (OSCC) cells promoted M2 macrophage polarization
ER stress is activated and positively relates to poor survival in OSCC patients To assess the effect of ER stress on OSCC progression, whether ER stress is upregulated among patients with OSCC was tested by the expression measurement of ER stress-associated proteins in 3 cases in which OSCC tissues had been surgically resected using immunohistochemistry
Summary
Endoplasmic reticulum (ER) stress has been found to foster the escape of cancer cells from immune surveillance and upregulate PD-L1 expression. Oral squamous cell carcinoma (OSCC) is the most usual kind of cancer of the head and neck area. Despite the recent progress in knowing the diagnosis, molecular biology, and treating OSCC, the associated five-year survival rate has been less than 50% for the past 30 years—primarily because of cases of metastasis or local incontrollable recurrence [1]. Other risk factors include infections with certain types of human papillomavirus, certain workplace exposures, and radiation exposure. The diagnosis is confirmed using a tissue biopsy, with computed tomography and blood tests often being used to check the degree of spread. Traditional treatments include surgery, chemotherapy, and radiation therapy [2, 3]
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