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Front Oncol. 2018 Sep 19;8:386. doi: 10.3389/fonc.2018.00386. eCollection 2018.

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

Author information

1
Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan.
2
Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
3
Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, United States.
4
Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, United States.

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.

KEYWORDS:

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

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