Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer

Gupta, Harshita; Clark, C. Brendan; Yuan, Bin; Sareddy, Gangadhara R.; Pandeswara, Srilakshmi; Padrón, Álvaro; Hurez, Vincent; Conejo-Garcia, José R.; Vadlamudi, Ratna K.; Li, Rong; Curiel, Tyler J.

doi:10.1038/sigtrans.2016.30

Cited by 89 publications

(78 citation statements)

References 32 publications

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“…29 Tumor cell-intrinsic PD-L1 was shown to promote tumor-initiating cell generation in OC. 30 Our data provided the first demonstration that PD-L1 serves as a crucial downstream effector of AKT3, and targeting PD-L1 might possibly retard the initiation and progression of OC induced by the EMX2OS/miR-654/AKT3 pathway, although this possibility requires further investigation.…”

Section: Discussionmentioning

confidence: 73%

<p>LncRNA EMX2OS Induces Proliferation, Invasion and Sphere Formation of Ovarian Cancer Cells via Regulating the miR-654-3p/AKT3/PD-L1 Axis</p>

Duan¹,

Fang²,

Wang³

et al. 2020

CMAR

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Long noncoding RNA (lncRNA) deregulation is frequent in human ovarian cancers (OCs), but the role of specific miRNAs involved in this disease remains elusive. LncRNA EMX2OS was previously reported to act as an oncogene in human cancers. However, their accurate expression, function and underlying mechanisms in OC are largely unclear. Materials and Methods: The levels of EMX2OS in OC tissues and cell lines were determined by quantitative real-time PCR, and the function of EMX2OS was then analyzed both in vitro and in vivo. Luciferase assays and immunoprecipitation assays were performed to analyze the association between EMX2OS and miR-654 expression in OC cells. Results: EMX2OS is overexpressed in human ovarian cancer tissues. Knockdown of EMX2OS reduced, while overexpression of EMX2OS enhanced the proliferation, invasion and sphere formation of OC cells. In addition, EMX2OS enhanced tumor growth in an in vivo xenograft model of human OC. We discovered that EMX2OS directly binds to miR-654 and suppresses its expression, thus leading to the upregulation of AKT3, which served as a direct target of miR-654. Moreover, miR-654 inhibited cell proliferation, invasion and sphere formation, and restoration of AKT3 reversed the effects of EMX2OS silencing or miR-654 overexpression. Furthermore, PD-L1 was identified as the key oncogenic component acting downstream of AKT3 in OC cells. Ectopic expression of PD-L1 reversed the anti-cancer functions by EMX2OS knockdown, AKT3 silencing or miR-654 upregulation in OC cells. Conclusion: These results demonstrated that the EMX2OS/miR-654/AKT3/PD-L1 axis confers aggressiveness in ovarian cancer and may represent a therapeutic target for OC metastasis.

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Section: Discussionmentioning

confidence: 73%

<p>LncRNA EMX2OS Induces Proliferation, Invasion and Sphere Formation of Ovarian Cancer Cells via Regulating the miR-654-3p/AKT3/PD-L1 Axis</p>

Duan¹,

Fang²,

Wang³

et al. 2020

CMAR

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“…CD133 + /PD-L1 + colorectal CSC cells showed the characteristic of EMT ( 96 ). Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation in melanoma and ovarian cancer ( 97 ). Similarly, PD-L1 promotes OCT4 and Nanog expression in breast CSCs through the activation of PI3K/AKT pathway ( 98 ).…”

Section: The Role Of Pd-l1 In Stimulating or Inhibiting Cancermentioning

confidence: 99%

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

et al. 2018

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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.

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“…It has been known for some time that PD-L1 had intrinsic signaling properties in cancer cells that protected that protected them from a range of apoptotic stimuli, and that its intracellular domain was required for this protection (Azuma et al, 2008). Moreover, PD-L1 was also shown to stimulate cancer cell growth by modulating the activity of AKT/mTOR, autophagy, and glycolysis (Chang et al, 2015;Clark et al, 2016;Gupta et al, 2016). The intracellular part of PD-L1 contains three nonclassical signaling motifs; The "RMLD," "DTSSK," and "QFEET" motifs ( Figure 1).…”

Section: Tumor-intrinsic Factors and Resistance To Pd-l1/pd-1 Blockadmentioning

confidence: 99%

Resistance to PD-L1/PD-1 Blockade Immunotherapy. A Tumor-Intrinsic or Tumor-Extrinsic Phenomenon?

et al. 2020

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Cancer immunotherapies targeting immune checkpoints such as programmed cell-death protein 1 (PD-1) and its ligand programmed cell-death 1 ligand 1 (PD-L1), are revolutionizing cancer treatment and transforming the practice of medical oncology. However, despite all the recent successes of this type of immunotherapies, most patients are still refractory and present either intrinsic resistance or acquired resistance. Either way, this is a major clinical problem and one of the most significant challenges in oncology. Therefore, the identification of biomarkers to predict clinical responses or for patient stratification by probability of response has become a clinical necessity. However, the mechanisms leading to PD-L1/PD-1 blockade resistance are still poorly understood. A deeper understanding of the basic mechanisms underlying resistance to cancer immunotherapies will provide insight for further development of novel strategies designed to overcome resistance and treatment failure. Here we discuss some of the major molecular mechanisms of resistance to PD-L1/PD-1 immune checkpoint blockade and argue whether tumor intrinsic or extrinsic factors constitute main determinants of response and resistance.

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Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer

Cited by 89 publications

References 32 publications

<p>LncRNA EMX2OS Induces Proliferation, Invasion and Sphere Formation of Ovarian Cancer Cells via Regulating the miR-654-3p/AKT3/PD-L1 Axis</p>

<p>LncRNA EMX2OS Induces Proliferation, Invasion and Sphere Formation of Ovarian Cancer Cells via Regulating the miR-654-3p/AKT3/PD-L1 Axis</p>

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

Resistance to PD-L1/PD-1 Blockade Immunotherapy. A Tumor-Intrinsic or Tumor-Extrinsic Phenomenon?

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