PD-1/PD-L1 interaction up-regulates MDR1/P-gp expression in breast cancer cells via PI3K/AKT and MAPK/ERK pathways

Liu, Shengwei; Chen, Shuang; Yuan, Weiguang; Wang, Hongyan; Chen, Kewang; Li, Dianjun; Li, Dalin

doi:10.18632/oncotarget.21914

Cited by 84 publications

(67 citation statements)

References 44 publications

(41 reference statements)

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“…Recruitment of SHP2 to the ITIM and ITSM cytoplasmic domains of PD-1 inhibits PI3K thus further blocks AKT phosphorylation and mTOR pathway ( 101 ). It is important to note that reports from cancer studies suggest that PD-1 engagement with PD-L1 does not cause dephosphorylation, but leads to phosphorylation and activation of AKT and ERK, which increases chemo resistance of the cancer cells ( 102 , 103 ), implying a difference in PD-1 signaling between chronic infection and cancer that requires further investigation. Through inhibiting these signaling molecules, PD-1 indirectly inhibits the production of cytokines including IL-2, hence interferes with T cell growth and function.…”

Section: Signaling Pathways and T-cell Exhaustionmentioning

confidence: 99%

T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses

et al. 2018

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T-cell exhaustion is a phenomenon of dysfunction or physical elimination of antigen-specific T cells reported in human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections as well as cancer. Exhaustion appears to be often restricted to CD8+ T cells responses in the literature, although CD4+ T cells have also been reported to be functionally exhausted in certain chronic infections. Although our understanding of the molecular mechanisms associated with the transcriptional regulation of T-cell exhaustion is advancing, it is imperative to also explore the central mechanisms that control the altered expression patterns. Targeting metabolic dysfunctions with mitochondrion-targeted antioxidants are also expected to improve the antiviral functions of exhausted virus-specific CD8+ T cells. In addition, it is crucial to consider the contributions of mitochondrial biogenesis on T-cell exhaustion and how mitochondrial metabolism of T cells could be targeted whilst treating chronic viral infections. Here, we review the current understanding of cardinal features of T-cell exhaustion in chronic infections, and have attempted to focus on recent discoveries, potential strategies to reverse exhaustion and reinvigorate optimal protective immune responses in the host.

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Section: Signaling Pathways and T-cell Exhaustionmentioning

confidence: 99%

T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses

et al. 2018

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“…CRISPR/Cas9 system-mediated PD-L1 disruption increased drug sensitivities for doxorubicin and paclitaxel ( 90 ). 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 ( 101 ).…”

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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“…PD-L1 is highly expressed in many malignant tumors ( 18 , 19 ). Studies have shown that PD-L1 may be regulated by oncogenes and various signaling pathways ( 20 – 23 ). High expression of PD-L1 can reduce the immune effect of T cells in the local microenvironment of the tumor, thus facilitating tumor escape and promoting tumor growth ( 24 , 25 ).…”

Section: Discussionmentioning

confidence: 99%

Antitumor effects of the silencing of programmed cell death ligand�1 in colorectal cancer via immunoregulation

Chen

Huang

et al. 2018

Oncol Rep

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Activation of programmed cell death 1 (PD-1)/PD-ligand 1 (PD-L1) can promote immune suppression of the tumor microenvironment. However, the effects and mechanisms of PD-L1 silencing on colorectal cancer growth are largely unknown. In the present study, PD-L1 expression was compared in colorectal cancer and paracancerous tissues by immunofluorescence. A stable colorectal carcinoma cell line encoding PD-L1 short hairpin RNA (shRNA) was established. Thereafter, inoculated tumors were modeled in C57B/L6 mice. Experiments were divided into 3 groups: Control group, vector group, and PD-L1 silencing group (inoculated with the stable CT26 cell line encoding PD-L1 shRNA). Following decapitation of the mice, tumors were weighed and apoptosis of tumor cells was detected. The number and viability of cluster of differentiation (CD)4+ and CD8+ T cells were analyzed by flow cytometry and a cell counting kit assay, respectively. Compared with paracancerous tissue, colorectal cancer tissue extensively expressed PD-L1, RAC-α serine/threonine-protein kinase (AKT), and phosphatidylinositol 3-kinase (PI3K). Lymphocyte-activating gene 3 (LAG-3) expression was observed at the edge of tumor tissue, but rarely observed in paracancerous tissue. A stable CT26 cell line encoding PD-L1 shRNA was established, and lack of PD-L1 expression was confirmed by reverse transcription-polymerase chain reaction and western blotting. Compared with the control, the shPD-L1 group demonstrated reduced tumor growth, a high level of apoptosis in tumor cells, a low level of PI3K and AKT expression, and an increased number of cells and greater activity of CD4+ T and CD8+ T cells. Taken together, PD-L1 silencing promoted tumor cell apoptosis, at least in part, through the activation of CD4+ and CD8+ T cells.

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PD-1/PD-L1 interaction up-regulates MDR1/P-gp expression in breast cancer cells via PI3K/AKT and MAPK/ERK pathways

Cited by 84 publications

References 44 publications

T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses

T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses

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

Antitumor effects of the silencing of programmed cell death ligand�1 in colorectal cancer via immunoregulation

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