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

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.

Figure 1

Mechanisms of PD-L1 activation in cancer. The diagram illustrates the diverse mechanisms of PD-L1 activation in cancer, including genetic alterations to PD-L1 (such as gene amplification, 3'-UTR disruption, or dysregulated transcription) and a wide range of epigenetic mechanisms (including upregulation of oncogenic microRNAs, downregulation of tumor suppressor microRNAs, aberrant DNA methylation and histone modifications).

Figure 2

Amplification and upregulation of PD-L1 and genes co-amplified with PD-L1 in TCGA data. (A) The Cancer Genome Atlas (TCGA) datasets in the cBioPortal database (www.cbioportal.org) was used to investigate molecular alterations (RNA expression, copy number variation, and mutation). Shown are OncoPrint outputs where each bar represents a tumor that was found to contain an alteration (amplification, deletion, mutation, upregulation, and downregulation, as indicated) in PD-L1, MYC, SOX2, N-cadherin (CDH2), and SNAI1 gene in samples of endometrial cancer (upper panel) and ovarian cancer (lower panel) based on TCGA data. (B) PD-L1 mRNA expression pattern was analyzed in a panel of cancer (red) vs. normal (green) tissues from the GENT database. (C) PD-L1 expression pattern was determined in multiple cancer microarray datasets available in the MethHC database. N, normal; C, cancer. **P < 0.005.

Figure 3

Tumor-intrinsic PD-L1 signaling in cancer initiation and development. The diagram illustrates signaling events downstream of PD-L1 activation in cancer. Although PD-L1 could serve as a tumor suppressor by inhibiting cancer stem cell properties in cholangiocarcinoma, it plays a pivotal role in promoting cancer stemness, EMT, tumor invasion, and chemoresistance in several tumor types. Importantly, activation of OCT4 signaling induces PD-L1 expression in cancer cells, thereby suggesting a possible immune evasion mechanism employed by cancer stem cells during metastasis.