Proinflammatory S100A8 Induces PD-L1 Expression in Macrophages, Mediating Tumor Immune Escape

  • J Immunol. 2020 May 1;204(9):2589-2599. doi: 10.4049/jimmunol.1900753.
Zhengshuo Li  1  2  3 ,  Jing Wang  4  5 ,  Xuemei Zhang  2  6 ,  Peishan Liu  2 ,  Xiaoyue Zhang  2 ,  Jia Wang  2 ,  Xiang Zheng  2 ,  Lingyu Wei  2 ,  Qiu Peng  2 ,  Can Liu  2 ,  Qun Yan  1  7 ,  Shourong Shen  4 ,  Xiayu Li  4 ,  Jian Ma  8  2  3  4
Affiliations
  • 1. Xiangya Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of the Ministry of Education, Central South University, Changsha, Hunan 410008, China.
  • 2. Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha 410078, China.
  • 3. NHC Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Central South University, Changsha 410078, China.
  • 4. Department of Gastroenterology, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
  • 5. Department of Gastroenterology, People's Hospital of Shimen County, Shimen, Hunan 415300, China.
  • 6. Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China; and.
  • 7. Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha 410008, China.
  • 8. Xiangya Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of the Ministry of Education, Central South University, Changsha, Hunan 410008, China; [email protected].
PMID: 32198140 DOI: 10.4049/jimmunol.1900753
Abstract

S100A8 is a damage-associated molecular pattern protein released by monocytes, playing a decisive role in the development of inflammation. Nonresolving inflammation is viewed as a driving force in tumorigenesis, and its role in tumor immune escape also attracted attentions. PD-1/PD-L1 axis is a critical determinant of physiological immune homeostasis, and anti-PD-1 or PD-L1 therapy has becoming the most exciting field of oncology. Multiple regulation mechanisms have been contributed to PD-L1 expression modulation including inflammatory mediators. In this study we reported that S100A8 significantly induced PD-L1 expression in monocytes/macrophages but not in tumor cells. S100A8 induced PD-L1 transcription through the TLR4 receptor and multiple crucial pathways of inflammation process. S100A8 modulated the histone modification of the PD-L1 promoter in monocytes/macrophages. S100A8-pretreated macrophages had immunosuppressive function and attenuated the antitumor ability of CTLs both in vitro and in vivo. A highly positive correlation existed between S100A8 expression and PD-L1 expression in human Cancer specimens. To our knowledge, our study uncovers a novel molecular mechanism for regulating PD-L1 transcription by an inflammatory mediator S100A8, and reveals the importance of comprehensive understanding the role of inflammation in tumorigenesis as well as in tumor immune escape.

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