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

Peixin Dong, Ying Xiong, Junming Yue and 2 more

Frontiers in Oncology · 2018 · Review

doi:10.3389/fonc.2018.00386

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.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 18, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

In cancer, the epithelial-to-mesenchymal transition (EMT) is a phenotypic process that promotes the acquisition of a mesenchymal features of epithelial tumor cells, reduces cell polarity and cell-cell adhesion, and enables them to migrate and invade more efficiently, by switching off the expression of epithelial markers, such as E-cadherin, and turning on mesenchymal markers, including N-cadherin and Vimentin. Epithelial tumor cells undergoing EMT are shown to contribute to tumorigenesis, invasion, metastasis, and resistance to chemotherapy, radiation and small-molecule-targeted therapy.

Cancer stem cells (CSCs) represent a fraction of undifferentiated cancer cells that are the seeds of tumor recurrence, have the ability to self-renew and exhibit significant resistance to conventional chemo- and radiotherapy. Emerging evidence has revealed an association between EMT and the acquisition of CSC-like properties. The induction of EMT program is a critical regulator of the CSC phenotype. On the other hand, tumors cells that exhibit the CSC phenotype also express genes associated with the EMT features and show enhanced metastatic ability, thus representing a novel mechanism contributing to cancer metastasis.

The mutual interactions between tumor cells and the tumor microenvironment are essential for tumorigenesis, tumor progression, metastasis and resistance to drug therapy. Tumor microenvironment consists of extracellular matrix and diverse cell populations such as T cells, NK cells, macrophages, dendritic cells, fibroblasts, and endothelial cells. Progression of cancer to an advanced or metastatic disease usually suggests a failure or insufficiency of the ongoing immune response. Tumors not only effectively escape immune recognition, they also actively inhibit T-cell-mediated normal anti-tumor activity to promote further tumor growth and metastasis by modulating immune checkpoints, which mediate immune tolerance and inhibit the anti-tumor immune response. Multiple checkpoint molecules, such as PD-1/PD-L1, CTLA4, BTLA, B7H3, B7H4, HHLA2, IDO1, Tim-3, CD28, CD40, CD47, CD70, CD137, VISTA, LAG-3, and TIGIT, have been reported. Among them, B7H3 has been identified as a critical promoter of tumor cell proliferation, migration, invasion, EMT, cancer stemness, and drug resistance.

PD-L1 (also known as CD274 or B7H1) is expressed in tumor cells and plays a crucial role in tumor immune escape and the formation of a permissive immune microenvironment, through at least three mechanisms: (i) tolerizing or anergizing tumor-reactive T cells by binding to its receptor PD-1; (ii) rendering tumor cells resistant to CD8+ T cell and Fas ligand-mediated lysis; and (iii) tolerizing T cells by reverse signaling through T cell-expressed CD80. In addition, PD-L1 is also expressed by tumor-associated myeloid-derived suppressor cells and macrophages, which are the major factors responsible for tumor-associated immune deficiencies.

Although PD-L1 is widely implicated in tumor immune evasion, the tumor-intrinsic roles of PD-L1 and the mechanisms by which PD-L1 regulates EMT, the acquisition of tumor-initiating potential and resistance to anti-tumor drugs, as well as the ability to disseminate and metastasize in human cancers are currently less well defined. As will be discussed in more detail below, the identification of tumor-intrinsic PD-L1 signaling may provide critical targets for the development of cancer therapies.

PD-L1 dysregulation and prognosis in cancer

An increasing number of studies suggested that PD-L1 is highly expressed in solid tumors, including colorectal cancer, lung cancer, pancreatic carcinoma, hepatocellular carcinoma, gastric cancer, ovarian cancer, endometrial cancer, and cervical cancer. High expression of PD-L1 was associated with significantly worse overall survival in cervical cancer, non-small cell lung cancer, gastric cancer, esophageal cancer, glioma, ovarian cancer, and other cancers. However, the prognostic value of PD-L1 for certain types of cancer is still controversial. Some studies reported that high PD-L1 could predict favorable prognosis. In cervical cancer, squamous cell carcinomas tended to express more PD-L1 than adenocarcinomas. The possible reasons for these inconsistent results might include cancer type (or subtypes), tumor heterogeneity, sample size, clinical stage, different intervention, the time point of PD-L1 measurement as well as the different methodology used in research (such as detection methods and procedures).

Mechanisms of PD-L1 activation in cancer

The tumor-intrinsic PD-L1 signaling pathway is inappropriately activated in many cancers. Mechanisms underlying aberrant PD-L1 activation mainly include genomic alterations (including copy number amplification and 3'-UTR disruption), constitutive oncogenic signaling activation, extrinsic factors and epigenetic mechanisms, such as upregulation of oncogenic microRNAs (miRNAs), downregulation of tumor suppressor miRNAs, aberrant DNA methylation, and histone modifications (Figure 1).

Copy number gain and 3′-UTR disruption

Small-cell lung cancer, squamous cell carcinoma of the oral cavity, cervical cancer, ovarian cancer, breast cancer, melanoma, bladder cancer, head and neck cancer, soft tissue sarcoma and prostate cancer exhibit increased copy number of chromosome 9p24, on which CD274 resides. Here, we investigated the frequency of elevated PD-L1 in ovarian cancer and endometrial cancer in The Cancer Genome Atlas (TCGA) data portal. Analysis of TCGA data by cBioPortal demonstrated that overall, PD-L1 was highly expressed in these two cancers, mainly including gene amplification and mRNA up-regulation (Figure 2A). Moreover, analyses of U133A and U133Plus2 datasets in the GENT (gene expression across normal and tumor tissue) database revealed that PD-L1 was highly overexpressed in many tumor tissues (Figure 2B). Furthermore, analysis of the TCGA dataset was performed by using the MethHC browser. PD-L1 mRNA expression was consistently upregulated across various cancers (Figure 2C). In addition, disruption of the 3' region of the PD-L1 increases mRNA stability, leading to a marked elevation of aberrant PD-L1 transcripts in multiple cancers.

Constitutive oncogenic signaling activation

Loss of PTEN expression, activation of PI3K/AKT pathway, activation of RAS/MAPK pathway, inhibition of p53 signaling, upregulation of reprogramming factors (Oct4, Sox2, and c-Myc) and upregulation of ZEB1 (an inducer of EMT) are clearly linked to the activation of PD-L1 signaling pathway (Figure 1).

PD-L1 expression could be regulated via the PI3K/AKT and/or RAS/MAPK pathways in different tumor cell types. PD-L1 expression is suppressed by the tumor suppressor gene PTEN. Deletion of PTEN gene results in elevated PD-L1 expression at the translational level by activating the PI3K/AKT signal pathway. FOXOs inhibit the expression of PD-L1 through repressing Myc or Wnt/β-catenin signaling pathways in tumor cells. MUC1 elevates PD-L1 transcription by recruitment of MYC and NF-κB (a downstream effector of PI3K/AKT pathway to the PD-L1 promoter in breast cancer. Also, MUC1 was shown to increase PD-L1 levels via downregulation of miR-34a and miR-200c, two direct suppressors of PD-L1.

Abnormal activation of stem cell signaling pathways has been implicated in the regulation of PD-L1. OCT4 is a key regulatory gene that maintains the self-renewal properties of CSC and promotes tumorigenesis of cervical cancer cells by miR-125b/BAK1pathway. We recently reported that, OCT4 promotes cervical cancer invasion and proliferation by enhancing PD-L1 expression through a miR-18a-dependent mechanism, by which miR-18a upregulates PD-L1 by targeting PTEN, WNK2 and SOX6 to activate the PI3K/AKT, MEK/ERK and Wnt/β-catenin pathways and inhibit the p53 pathway. In addition, SOX2, a transcription factor that controls tumor initiation and cancer stem-cell functions, can directly bind to the PD-L1 promoter and transactive its expression, contributing to the increased proliferation of hepatocellular carcinoma cells. The upstream kinases of the Hippo pathway MST1/2 and LATS1/2 suppress PD-L1 expression, while TAZ and YAP enhance PD-L1 levels in breast and lung cancer cells.

Tumor cells undergoing EMT are shown to share a variety of capabilities with experimentally defined CSC. In lung cancer, PD-L1 expression was significantly higher in patients with EMT phenotypes (such as increased SNAI1 and Vimentin expression) compared with those with epithelial phenotypes. siRNA-mediated ZEB1 knockdown suppressed PD-L1 expression but promoted E-cadherin expression in esophageal squamous cell carcinoma. In agreement with these reports, cBioportal analysis of data on somatic copy number variation and mRNA level using TCGA endometrial and ovarian cancer dataset demonstrated that PD-L1 is indeed co-amplified along with MYC, SOX2, N-cadherin and SNAI1 in both cancer types (Figure 2A).

Another study reported that transcription factor NKX2-1 bound to the locus of PD-L1 and induced its expression in mucinous lung cancer cells. In non-small cell lung cancer cells, the ubiquitin ligases Cbl-b and c-Cbl inhibit PD-L1 expression by inactivating STAT, AKT, and ERK signaling, and overexpression of tumor suppressor gene TUSC2 downregulated PD-L1 expression. CDK4 and CDK6 kinase destabilize PD-L1 protein via cullin 3–SPOP, leading to the downregulation of PD-L1 in cancer cells.

Regulation of PD-L1 expression by epigenetic mechanisms

The expression of cancer-associated genes can occur by epigenetic mechanisms, including DNA methylation, histone modification, chromatin remodeling, and non-coding RNAs. The anti-PD-1 therapy could induce PD-L1 promoter methylation and decrease PD-L1 levels in patients with non-small cell lung cancer. The class I histone deacetylase HDAC8 acts as an epigenetic inhibitor of PD-L1 expression in melanoma cells via modulating HOXA5 and STAT3. Numerous miRNAs, including miR-15a/miR-16, miR-17-5p, miR-93/106b, miR-138-5p, miR-140/miR-142/miR-340/miR-383, miR-152, miR-155, miR-193, miR-195, miR-324-5p/miR-338 and miR-322/miR-424, have been shown to directly target and inhibit PD-L1 expression in tumor cells. In chemo-resistant non-small-cell lung cancer cells, miR-197 indirectly inhibits PD-L1 expression by regulating the CKS1B/STAT3 axis. On the other hand, oncogenic miR-20b and miR-21 inhibited PTEN expression, resulting in PD-L1 overexpression in colorectal cancer. Our recent data established that an oncogenic OCT4-miR-18a pathway serves as the key upstream activator of PD-L1 in cervical cancer.

Extrinsic factors influencing the expression of PD-L1

The main regulators of PD-L1 are the interferon-γ, inflammatory cytokines such as IL-17 and TNF-α, TGF-β1, and HIF-1α. Of note, overexpressing HPV16E7 oncoprotein increased PD-L1 protein expression, and knockdown of HPV16E7 resulted in a reduction in PD-L1 protein expression in cancer cells. Consistent with this data, PD-L1 protein expression was significantly higher in the normal cervical tissues with HPV infection than those normal cervical tissues without HPV infection. Estrogen is a well-known oncogenic driver of endometrial and breast cancer, and it upregulates PD-L1 protein expression in ERα-positive endometrial and breast cancer cells.

The role of PD-L1 in stimulating or inhibiting cancer

A tumor-intrinsic role for PD-L1 in promoting cancer initiation, metastasis, development, and resistance to therapy is emerging (Figure 3). For instance, knockdown of PD-L1 expression in gastric cancer cells could significantly suppress cell proliferation, migration and invasion. Also, knockout of PD-L1 expression by CRISPR/Cas9 inhibits the spheroid formation of osteosarcoma cells. PD-L1 was shown to promote EMT in esophageal cancer. Knockdown of PD-L1 expression significantly suppressed tumor growth in nude mice in gastric cancer and cervical cancer model.

Interestingly, a link between PD-L1 expression and EMT/CSC-like phenotypes has been reported. For example, bladder cancer cells with surface expression of PD-L1 exhibited signatures of immune evasion as well as increased stemness. PD-L1 has been shown to be preferentially expressed on CD44high CSCs in lung cancer cells. Selective expression of PD-L1 was observed on CD44+ head and neck tumor cells compared with CD44− tumor cells. CD133+/PD-L1+ colorectal CSC cells showed the characteristic of EMT. Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation in melanoma and ovarian cancer. Similarly, PD-L1 promotes OCT4 and Nanog expression in breast CSCs through the activation of PI3K/AKT pathway.

Moreover, PD-L1 overexpression promotes EMT and invasion in glioblastoma multiforme via RAS/ERK/EMT activation. RNA-sequencing analysis of glioblastoma multiforme revealed that PD-L1 significantly altered the expression of genes, which were enriched in cell growth/migration/invasion pathways. PD-L1 induced EMT via activating SREBP-1c in renal cell carcinoma. CRISPR/Cas9 system-mediated PD-L1 disruption increased drug sensitivities for doxorubicin and paclitaxel. The interaction of PD-L1 with PD-1 induced phosphorylation of AKT and ERK, resulting in the activation of PI3K/AKT and MAPK/ERK pathways and increased MDR1 expression in breast cancer cells.

However, depletion of PD-L1 expression by shRNA in cholangiocarcinoma cells enhances their tumorigenicity and increases ALDH activity, and patients with lower PD-L1 expression shows poorer prognosis when compared with those with higher PD-L1 expression, indicating that PD-L1 may also have anti-tumor effects by inhibiting cancer stemness under certain circumstances.

Conclusions

It is becoming clear that, although PD-L1 could serve as a tumor suppressor by inhibiting cancer stem cell properties in cholangiocarcinoma, tumor cell-intrinsic PD-L1 plays a pivotal role in promoting cancer stemness, EMT, tumor invasion, and chemoresistance in several tumor types. Importantly, 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. The continued characterization of immune-independent PD-L1 functions and identification of crucial signaling events upstream or downstream of PD-L1 in diverse cancer types (or specific cancer subtypes), would provide additional targets and new therapeutic approaches.

Author contributions

PD and HW provided direction. PD, YX, and HW wrote the manuscript. JY and SH made significant revisions to the manuscript. All authors read and approved the final manuscript.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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    Tsutsumi S Saeki H Nakashima Y Ito S Oki E Morita M. Programmed death-ligand 1 expression at tumor invasive front is associated with epithelial-mesenchymal transition and poor prognosis in esophageal squamous cell carcinoma. Cancer Sci. (2017 ) 108:1119–27.

    Not in our library10.1111/cas.13237

  64. 64.

    Guo M Tomoshige K Meister M Muley T Fukazawa T Tsuchiya T. Gene signature driving invasive mucinous adenocarcinoma of the lung. EMBO Mol Med. (2017 ) 9:462–81.

    Not in our library10.15252/emmm.201606711

  65. 65.

    Wang S Xu L Che X Li C Xu L Hou K. E3 ubiquitin ligases Cbl-b and c-Cbl downregulate PD-L1 in EGFR wild-type non-small cell lung cancer. FEBS Lett. (2018 ) 592:621–30.

    Not in our library10.1002/1873-3468.12985

  66. 66.

    Cao X Zhao Y Wang J Dai B Gentile E Lin J. TUSC2 downregulates PD-L1 expression in non-small cell lung cancer (NSCLC). Oncotarget (2017 ) 8:107621–9.

    Not in our library10.18632/oncotarget.22581

  67. 67.

    Zhang J Bu X Wang H Zhu Y Geng Y Nihira NT. Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature (2018 ) 553:91–5.

    Not in our library10.1038/nature25015

  68. 68.

    Dong P Xiong Y Watari H Hanley SJ Konno Y Ihira K. Suppression of iASPP-dependent aggressiveness in cervical cancer through reversal of methylation silencing of microRNA-124. Sci Rep. (2016 ) 6:35480.

    Not in our library10.1038/srep35480

  69. 69.

    Ihira K Dong P Xiong Y Watari H Konno Y Hanley SJ. EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis. Oncotarget (2017 ) 8:13509–20.

    Not in our library10.18632/oncotarget.14586

  70. 70.

    Dong P Ihira K Xiong Y Watari H Hanley SJ Yamada T. Reactivation of epigenetically silenced miR-124 reverses the epithelial-to-mesenchymal transition and inhibits invasion in endometrial cancer cells via the direct repression of IQGAP1 expression. Oncotarget (2016 ) 7:20260–70.

    Not in our library10.18632/oncotarget.7754

  71. 71.

    Zhang Y Xiang C Wang Y Duan Y Liu C Zhang Y. PD-L1 promoter methylation mediates the resistance response to anti-PD-1 therapy in NSCLC patients with EGFR-TKI resistance. Oncotarget (2017 ) 8:101535–44.

    Not in our library10.18632/oncotarget.21328

  72. 72.

    Wang YF Liu F Sherwin S Farrelly M Yan XG Croft A. Cooperativity of HOXA5 and STAT3 is critical for HDAC8 inhibition-mediated transcriptional activation of PD-L1 in human melanoma cells. J Invest Dermatol. (2018 ) 138:922–32.

    Not in our library10.1016/j.jid.2017.11.009

  73. 73.

    Kao SC Cheng YY Williams M Kirschner MB Madore J Lum T. Tumor suppressor microRNAs contribute to the regulation of PD-L1 expression in malignant pleural mesothelioma. J Thorac Oncol. (2017 ) 12:1421–33.

    Not in our library10.1016/j.jtho.2017.05.024

  74. 74.

    Audrito V Serra S Stingi A Orso F Gaudino F Bologna C. PD-L1 up-regulation in melanoma increases disease aggressiveness and is mediated through miR-17-5p. Oncotarget (2017 ) 8:15894–911.

    Not in our library10.18632/oncotarget.15213

  75. 75.

    Cioffi M Trabulo SM Vallespinos M Raj D Kheir TB Lin ML. The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1. Oncotarget (2017 ) 8:21609–25.

    Not in our library10.18632/oncotarget.15450

  76. 76.
    The tumor suppressor miR-138-5p targets PD-L1 in colorectal cancer · 2016
    No notice
  77. 77.

    Wang Y Wang D Xie G Yin Y Zhao E Tao K. MicroRNA-152 regulates immune response via targeting B7-H1 in gastric carcinoma. Oncotarget (2017 ) 8:28125–34.

    Not in our library10.18632/oncotarget.15924

  78. 78.
    MicroRNA-155 induction via TNF-α and IFN-γ suppresses expression of programmed death ligand-1 (PD-L1) in human primary cells · 2017
    No notice
  79. 79.

    Holla S Stephen-Victor E Prakhar P Sharma M Saha C Udupa V. Mycobacteria-responsive sonic hedgehog signaling mediates programmed death-ligand 1- and prostaglandin E2-induced regulatory T cell expansion. Sci Rep. (2016 ) 6:24193.

    Not in our library10.1038/srep24193

  80. 80.
    miR-424(322) reverses chemoresistance via T-cell immune response activation by blocking the PD-L1 immune checkpoint · 2016
    No notice
  81. 81.
    The Clinical Relevance of the miR-197/CKS1B/STAT3-mediated PD-L1 Network in Chemoresistant Non-small-cell Lung Cancer · 2015
    No notice
  82. 82.

    Zhu J Chen L Zou L Yang P Wu R Mao Y. MiR-20b,−21, and−130b inhibit PTEN expression resulting in B7-H1 over-expression in advanced colorectal cancer. Hum Immunol. (2014 ) 75:348–53.

    Not in our library10.1016/j.humimm.2014.01.006

  83. 83.

    Garcia-Diaz A Shin DS Moreno BH Saco J Escuin-Ordinas H Rodriguez GA. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. (2017 ) 19:1189–201.

    Not in our library10.1016/j.celrep.2017.04.031

  84. 84.

    Wang X Yang L Huang F Zhang Q Liu S Ma L. Inflammatory cytokines IL-17 and TNF-α up-regulate PD-L1 expression in human prostate and colon cancer cells. Immunol Lett. (2017 ) 184:7–14.

    Not in our library10.1016/j.imlet.2017.02.006

  85. 85.
    Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: Significance in claudin-low breast cancer cells · 2015
    No notice
  86. 86.

    Noman MZ Desantis G Janji B Hasmim M Karray S Dessen P. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. (2014 ) 211:781–90.

    Not in our library10.1084/jem.20131916

  87. 87.

    Liu C Lu J Tian H Du W Zhao L Feng J Increased expression of PD-L1 by the human papillomavirus 16 E7 oncoprotein inhibits anticancer immunity. Mol Med Rep. (2017 ) 15:1063–70.

    Not in our library10.3892/mmr.2017.6102

  88. 88.

    Yang L Huang F Mei J Wang X Zhang Q Wang H. Posttranscriptional control of PD-L1 expression by 17β-estradiol via PI3K/Akt signaling pathway in ERα-Positive Cancer Cell Lines. Int J Gynecol Cancer (2017 ) 27:196–205.

    Not in our library10.1097/igc.0000000000000875

  89. 89.

    Li J Chen L Xiong Y Zheng X Xie Q Zhou Q. Knockdown of PD-L1 in human gastric cancer cells inhibits tumor progression and improves the cytotoxic sensitivity to CIK therapy. Cell Physiol Biochem. (2017 ) 41:907–20.

    Not in our library10.1159/000460504

  90. 90.

    Liao Y Chen L Feng Y Shen J Gao Y Cote G. Targeting programmed cell death ligand 1 by CRISPR/Cas9 in osteosarcoma cells. Oncotarget (2017 ) 8:30276–87.

    Not in our library10.18632/oncotarget.16326

  91. 91.

    Chen L Xiong Y Li J Zheng X Zhou Q Turner A. PD-L1 expression promotes epithelial to mesenchymal transition in human esophageal cancer. Cell Physiol Biochem. (2017 ) 42:2267–80.

    Not in our library10.1159/000480000

  92. 92.

    Li Y Yang X Wu Y Zhao K Ye Z Zhu J. B7-H3 promotes gastric cancer cell migration and invasion. Oncotarget (2017 ) 8:71725–35.

    Not in our library10.18632/oncotarget.17847

  93. 93.

    Jinesh GG Manyam GC Mmeje CO Baggerly KA Kamat AM. Surface PD-L1, E-cadherin, CD24, and VEGFR2 as markers of epithelial cancer stem cells associated with rapid tumorigenesis. Sci Rep. (2017 ) 7:9602.

    Not in our library10.1038/s41598-017-08796-z

  94. 94.

    Nishino M Ozaki M Hegab AE Hamamoto J Kagawa S Arai D. Variant CD44 expression is enriching for a cell population with cancer stem cell-like characteristics in human lung adenocarcinoma. J Cancer (2017 ) 8:1774–85.

    Not in our library10.7150/jca.19732

  95. 95.

    Lee Y Shin JH Longmire M Wang H Kohrt HE Chang HY. CD44+ cells in head and neck squamous cell carcinoma suppress T-cell-mediated immunity by selective constitutive and inducible expression of PD-L1. Clin Cancer Res. (2016 ) 22:3571–81.

    Not in our library10.1158/1078-0432.ccr-15-2665

  96. 96.
    B7H1 Expression and Epithelial-To-Mesenchymal Transition Phenotypes on Colorectal Cancer Stem-Like Cells. · 2015
    Not checked
  97. 97.

    Gupta HB Clark CA Yuan B Sareddy G Pandeswara S Padron AS. Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer. Signal Transduct Target Ther (2016 ) 1:16030.

    Not in our library10.1038/sigtrans.2016.30

  98. 98.

    Almozyan S Colak D Mansour F Alaiya A Al-Harazi O Qattan A. PD-L1 promotes OCT4 and Nanog expression in breast cancer stem cells by sustaining PI3K/AKT pathway activation. Int J Cancer (2017 ) 141:1402–12.

    Not in our library10.1002/ijc.30834

  99. 99.

    Qiu XY Hu DX Chen WQ Chen RQ Qian SR Li CY. PD-L1 confers glioblastoma multiforme malignancy via Ras binding and Ras/Erk/EMT activation. Biochim Biophys Acta (2018 ) 1864(5 Pt A):1754–69.

    Not in our library10.1016/j.bbadis.2018.03.002

  100. 100.

    Wang Y Wang H Zhao Q Xia Y Hu X Guo J. PD-L1 induces epithelial-to-mesenchymal transition via activating SREBP-1c in renal cell carcinoma. Med Oncol. (2015 ) 32:212.

    Not in our library10.1007/s12032-015-0655-2

  101. 101.

    Liu S Chen S Yuan W Wang H Chen K Li D. PD-1/PD-L1 interaction up-regulates MDR1/P-gp expression in breast cancer cells via PI3K/AKT and MAPK/ERK pathways. Oncotarget (2017 ) 8:99901–12.

    Not in our library10.18632/oncotarget.21914

  102. 102.

    Tamai K Nakamura M Mizuma M Mochizuki M Yokoyama M Endo H. Suppressive expression of CD274 increases tumorigenesis and cancer stem cell phenotypes in cholangiocarcinoma. Cancer Sci. (2014 ) 105:667–74.

    Not in our library10.1111/cas.12406

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