The nuclear transportation of PD-L1 and the function in tumor immunity and progression

Qu, Lin; Jin, Jiakang; Lou, Jianan; Qian, Chao Nan; Lin, Jinti; Xu, Ankai; Liu, Bing; Zhang, Man; Tao, Huimin; Yu, Wei

doi:10.1007/s00262-022-03176-7

Cited by 7 publications

(12 citation statements)

References 97 publications

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“…They demonstrate that deletion of the C‐tail prevents PD‐L1 nuclear translocation, and interfering with PD‐L1 acetylation through genetic or pharmacological means inhibits its nuclear translocation. Additionally, vimentin has been described as a shuttle for PD‐L1 nuclear transport [ 22 ]. It has a positive relationship with PD‐L1 expression and promotes the epithelial‐mesenchymal transition (EMT) [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

“…Both, cell cycle inhibition and irradiation, lead to a differential cellular translocation of PD‐L1 [ 21 ]. This observed effect could reduce the efficacy of immunotherapy and promote tumor cell resistance [ 22 ]. Recent studies have shown a correlation between PD‐L1 expression in tumor cells and the response to PD‐1/PD‐L1 blockade [ 23 , 24 ], while also the specific cellular localization of PD‐L1 may play an important role.…”

Section: Introductionmentioning

confidence: 99%

“…Inside the nucleus, PD‐L1 interacts with proteins involved in mRNA splicing and DNA remodeling. Recently, there have been some new publications investigating the translocation of PD‐L1 into the nucleus [ 22 , 27 , 28 ], where it appears to be involved in sister chromatid segregation [ 28 ]. Deacetylation of PD‐L1 on the plasma membrane enables its binding with HIP1R and AP2B1 for endocytosis.…”

Section: Introductionmentioning

confidence: 99%

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Subcellular localization of PD‐L1 and cell‐cycle‐dependent expression of nuclear PD‐L1 variants: implications for head and neck cancer cell functions and therapeutic efficacy

Schulz,

Feulner,

Santos Rubenich

et al. 2023

Molecular Oncology

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The programmed cell death 1 ligand 1 (PD‐L1)/programmed cell death protein 1 (PD‐1) axis is primarily associated with immunosuppression in cytotoxic T lymphocytes (CTLs). However, mounting evidence is supporting the thesis that PD‐L1 not only functions as a ligand but mediates additional cellular functions in tumor cells. Moreover, it has been demonstrated that PD‐L1 is not exclusively localized at the cellular membrane. Subcellular fractionation revealed the presence of PD‐L1 in various cellular compartments of six well‐characterized head and neck cancer (HNC) cell lines, including the nucleus. Via Western blotting, we detected PD‐L1 in its well‐known glycosylated/deglycosylated state at 40–55 kDa. In addition, we detected previously unknown PD‐L1 variants with a molecular weight at approximately 70 and > 150 kDa exclusively in nuclear protein fractions. These in vitro findings were confirmed with primary tumor samples from head and neck squamous cell carcinoma (HNSCC) patients. Furthermore, we demonstrated that nuclear PD‐L1 variant expression is cell‐cycle‐dependent. Immunofluorescence staining of PD‐L1 in different cell cycle phases of synchronized HNC cells supported these observations. Mechanisms of nuclear PD‐L1 trafficking remain less understood; however, proximity ligation assays showed a cell‐cycle‐dependent interaction of the cytoskeletal protein vimentin with PD‐L1, whereas vimentin could serve as a potential shuttle for nuclear PD‐L1 transportation. Mass spectrometry after PD‐L1 co‐immunoprecipitation, followed by gene ontology analysis, indicated interaction of nuclear PD‐L1 with proteins involved in DNA remodeling and messenger RNA (mRNA) splicing. Our results in HNC cells suggest a highly complex regulation of PD‐L1 and multiple tumor cell‐intrinsic functions, independent of immune regulation. These observations bear significant implications for the therapeutic efficacy of immune checkpoint inhibition.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Subcellular localization of PD‐L1 and cell‐cycle‐dependent expression of nuclear PD‐L1 variants: implications for head and neck cancer cell functions and therapeutic efficacy

Schulz,

Feulner,

Santos Rubenich

et al. 2023

Molecular Oncology

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“…They are slightly different in structure, but also play important roles in the process of immunosuppression. nPD-L1 promotes tumor cell proliferation through chromatin remodeling process 43 . cPD-L1 can be transported to the cell surface to replenish mPD-L1 recognized by antibodies, leading to the failure of antibody therapy 44 .…”

Section: Structure Functions and Regulation Of Pd-l1mentioning

confidence: 99%

Strategies targeting PD-L1 expression and associated opportunities for cancer combination therapy

Yin¹,

Chen²,

Chen³

et al. 2023

Theranostics

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Immunotherapy has achieved great success recently and opened a new avenue for anti-tumor treatment. Programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) are typical immune checkpoints that transmit coinhibitory signals, muting the host immunity. Monoclonal antibodies that block PD-1/PD-L1 axis have benefited many patients with different tumor diseases. However, the objective response rate is still unsatisfactory. In this review, we summarize three strategies targeting PD-L1 based on different forms of PD-L1 and various regulating mechanisms to enhance the therapeutic effect, including blockade of the interaction between PD-L1 and PD-1, downregulation of PD-L1 expression and degradation of mature PD-L1. Thereinto, we describe a variety of materials have been designed to target PD-L1, including antibodies, nanoparticle, peptide, aptamer, RNA, and small molecule. Additionally, we list the drugs with PD-L1 regulation capacity used in clinical and ongoing studies to explore other alternatives for targeting PD-L1 besides anti-PD-L1 monoclonal antibodies. Moreover, we discuss associated opportunities for cancer combination therapy with other modalities such as chemotherapy, radiotherapy, photodynamic therapy (PDT) and photothermal therapy (PTT), as these conventional or emerging modalities are capable of increasing the immune response of tumor cells by altering the tumor microenvironment (TME), and would display synergistic effect. At last, we give a brief summary and outlook regarding the research status and future prospect of immunotherapy.

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“…Programmed death ligand-1 (PD-L1), encoded by the CD274 gene, is an immune checkpoint inhibitor that, when expressed on the surface of tumor or on antigen presenting cells (APC), binds to programmed death-1 (PD-1) on T lymphocytes, inhibiting their immune function. Such interactions activate Src homology region 2 domain-containing phosphatases (SPH2), leading to suppression of the T-cell receptor (TCR) signaling pathway [ 1 ]. Blocking the PD-L1/PD-1 interaction represents a promising strategy to restore T cell immunity and improve the outcome of several anti-cancer therapies [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Acetylation increases expression, interaction with TRAPPC4 and surface localization of PD-L1

Romeo,

Gilardini Montani,

Santarelli

et al. 2023

Discov Onc

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PD-L1 is an immune checkpoint inhibitor, whose surface expression may be exploited by cancer cells to escape T cell-mediated immune recognition. PD-L1 expression and nuclear localization can be affected by epigenetic modifications, such as acetylation. In this study, we showed that VPA, a class I/IIa HDAC inhibitor, upregulated PD-L1 expression on the surface of pancreatic cancer cells. To this effect contributed the increased transcription, in correlation with histone acetylation of the PD-L1 gene and the acetylation of PD-L1 protein, which led to an increased interaction with TRAPPC4, molecule involved in PD-L1 recycling to the cell membrane. Interestingly, the BRD4 inhibitor JQ-1, counteracted PD-L1 transcription and reduced its surface expression, suggesting that such a combination could improve the outcome of VPA treatment, also because it increased the cytotoxic effect of VPA. Also considering that this HDACi did not upregulate PD-L2 and that the supernatant of VPA-treated cancer cells did not increase PD-L1 expression on the surface of macrophages exposed to it.

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The nuclear transportation of PD-L1 and the function in tumor immunity and progression

Cited by 7 publications

References 97 publications

Subcellular localization of PD‐L1 and cell‐cycle‐dependent expression of nuclear PD‐L1 variants: implications for head and neck cancer cell functions and therapeutic efficacy

Subcellular localization of PD‐L1 and cell‐cycle‐dependent expression of nuclear PD‐L1 variants: implications for head and neck cancer cell functions and therapeutic efficacy

Strategies targeting PD-L1 expression and associated opportunities for cancer combination therapy

Acetylation increases expression, interaction with TRAPPC4 and surface localization of PD-L1

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