Tumor-Intrinsic PD-L1 Signaling in Cancer Initiation, Development and Treatment: Beyond Immune Evasion.

Peixin Dong* (Corresponding Author), Ying Xiong, Junming Yue, Sharon J. B. Hanley, Hidemichi Watari

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

185 Citations (Scopus)
3 Downloads (Pure)

Abstract

Although the role of PD-L1 in suppressing the anti-tumor immune response is extensively documented, recent discoveries indicate a distinct tumor-intrinsic role for PD-L1 in modulating epithelial-to-mesenchymal transition (EMT), cancer stem cell (CSC)-like phenotype, metastasis and resistance to therapy. In this review, we will focus on the newly discovered functions of PD-L1 in the regulation of cancer development, describe underlying molecular mechanisms responsible for PD-L1 upregulation and discuss current insights into novel components of PD-L1 signaling. Furthermore, we summarize our current understanding of the link between PD-L1 signaling and the EMT program as well as the CSC state. Tumor cell-intrinsic PD-L1 clearly contributes to cancer stemness, EMT, tumor invasion and chemoresistance in multiple tumor types. Conversely, activation of OCT4 signaling and upregulation of EMT inducer ZEB1 induce PD-L1 expression in cancer cells, thereby suggesting a possible immune evasion mechanism employed by cancer stem cells during metastasis. Our meta-analysis demonstrated that PD-L1 is co-amplified along with MYC, SOX2, N-cadherin and SNAI1 in the TCGA endometrial and ovarian cancer datasets. Further identification of immune-independent PD-L1 functions and characterization of crucial signaling events upstream or downstream of PD-L1 in diverse cancer types and specific cancer subtypes, would provide additional targets and new therapeutic approaches.
Original languageEnglish
Article number386
Number of pages8
JournalFrontiers in Oncology
Volume8
DOIs
Publication statusPublished - 19 Sept 2018

Bibliographical note

Funding: This work was supported by a grant from JSPS Grant-in-Aid for Scientific Research (C) (16K11123 and 18K09278) and the Science and Technology Planning Project of Guangdong Province, China (2014A020212124).

Keywords

  • cancer stem cells
  • metastasis
  • microRNA
  • EMT
  • CD274
  • PD-L1

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