Endoplasmic reticulum stress promotes the release of exosomal PD-L1 from head and neck cancer cells and facilitates M2 macrophage polarization

• Published in: Cell communication and signaling 2022-01, Vol.20 (1), p.12-12, Article 12
• Main Authors: Yuan, Yi, Jiao, Pengfei, Wang, Zeyu, Chen, Mengqi, Du, Hongming, Xu, Liang, Xu, Juanyong, Dai, Youjin, Wu, Fu-Gen, Zhang, Yaqin, Wu, Heming
• Format: Article
• Language: English
• Subjects: Activating transcription factor 6; Animals; B7-H1 Antigen - metabolism; Cancer therapies; Cell culture; Cytokines; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Exosome; Exosomes; Head & neck cancer; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Immunofluorescence; Immunosurveillance; Kinases; Macrophage; Macrophages; Macrophages - metabolism; Macrophages - pathology; Metastases; Metastasis; Mice; Mice, Nude; Mouth Neoplasms - metabolism; Mouth Neoplasms - pathology; Oral carcinoma; Oral squamous cell carcinoma; PD-L1; PD-L1 protein; Polarization; Proteins; Radiation; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - metabolism; Squamous Cell Carcinoma of Head and Neck - pathology; Tumors; Western blotting
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-021-00810-2

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. 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. 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. 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. Exosomal PD-L1 secreted by ER-stressed OSCC cells promoted M2 macrophage polarization. Video Abstract.