Journal
CELL COMMUNICATION AND SIGNALING
Volume 20, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s12964-021-00810-2
Keywords
Oral squamous cell carcinoma; Macrophage; Endoplasmic reticulum stress; Exosome; PD-L1
Categories
Funding
- Foundation of Jiangsu Province, China [BK20151562]
- Nanjing Science and technology planning project [201715016]
- Open Research Fund of State Key Laboratory of Bioelectronics, Southeast University [Sklb2021p02]
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ER stress upregulates PD-L1 expression and promotes M2 polarization in macrophages in oral squamous cell carcinoma (OSCC). A new exosome-modulated mechanism for OSCC-macrophage crosstalk driving tumor development was delineated.
Background: Endoplasmic 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. Methods: While 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. Results: The 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. Conclusions: ER 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.
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