PD-L1: expression regulation

Zhou, Yujie; Li, Guoli; Wang, Jiyin; Liu, Mengyuan; Wang, Zihan; Song, Yu; Zhang, Xulong; Wang, Xi

doi:10.1097/bs9.0000000000000149

Cited by 20 publications

(12 citation statements)

References 243 publications

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“…We also found that CTL infiltration in the SHMT2 low-expression group suggested a good prognosis, whereas CTL infiltration in the SHMT2 high-expression group suggested a poor prognosis, suggesting that SHMT2 is associated with T cell depletion. Several studies have reported that SHMT2 is significantly and positively correlated with PD-L1 expression (Wu et al 2019 ; Zhou et al 2023b ). PD-L1 inhibits T cell responses by activating the downstream signaling pathway of the PD-1 receptor, reducing T cell activity and promoting apoptosis, thereby inhibiting T cell responses and leading to tumor immune escape.…”

Section: Discussionmentioning

confidence: 99%

Construction and validation of a folate metabolism-related gene signature for predicting prognosis in HNSCC

Wang,

He,

Bai

et al. 2024

J Cancer Res Clin Oncol

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Purpose Metabolic reprogramming is currently considered a hallmark of tumor and immune development. It is obviously of interest to identify metabolic enzymes that are associated with clinical prognosis in head and neck squamous cell carcinomas (HNSCC). Methods Candidate genes were screened to construct folate metabolism scores by Cox regression analysis. Functional enrichment between high- and low-folate metabolism groups was explored by GO, KEGG, GSVA, and ssGSEA. EPIC, MCPcounter, and xCell were utilized to explore immune cell infiltration between high- and low-folate metabolism groups. Relevant metabolic scores were calculated and visually analyzed by the “IOBR” software package. Results To investigate the mechanism behind metabolic reprogramming of HNSCC, 2886 human genes associated with 86 metabolic pathways were selected. Folate metabolism is significantly enriched in HNSCC, and that the six-gene (MTHFD1L, MTHFD2, SHMT2, ATIC, MTFMT, and MTHFS) folate score accurately predicts and differentiates folate metabolism levels. Reprogramming of folate metabolism affects CD8T cell infiltration and induces immune escape through the MIF signaling pathway. Further research found that SHMT2, an enzyme involved in folate metabolism, inhibits CD8T cell infiltration and induces immune escape by regulating the MIF/CD44 signaling axis, which in turn promotes HNSCC progression. Conclusions Our study identified a novel and robust folate metabolic signature. A folate metabolic signature comprising six genes was effective in assessing the prognosis and reflecting the immune status of HNSCC patients. The target molecule of folate metabolic reprogramming, SHMT2, probably plays a very important role in HNSCC development and immune escape.

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Section: Discussionmentioning

confidence: 99%

Construction and validation of a folate metabolism-related gene signature for predicting prognosis in HNSCC

Wang,

He,

Bai

et al. 2024

J Cancer Res Clin Oncol

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“…Notwithstanding the fact that PD-L1 expression correlates with disease stage and prognosis in some tumoral contexts, among which lung adenocarcinoma, nasopharyngeal carcinoma and non-small cell lung cancer ( Nie et al, 2021 ; Zhou et al, 2023 ), the relationship between surface PD-L1 and disease parameters remains largely unknown. Here we demonstrated that leukemic cells from U-CLL patients, that develop aggressive forms of the disease ( Kipps et al, 2017 ), as well as from Eμ-TCL1 mice with overt leukemia, express the highest surface amounts of PD-L1 and harbor the most relevant IS-suppressive activity.…”

Section: Discussionmentioning

confidence: 99%

“…Genetic aberrations, such as ionizing radiation-induced double strand breaks, have been implicated in PD-L1 overexpression in cancer cells ( Zhou et al, 2023 ). Moreover, pro-inflammatory stimuli such as interferons, as well as altered oncogenic signaling pathways, among which the Ras/mitogen activated protein kinase (MAPK) and the Phosphatidyl inositol-3-kinase (PI3K)/Akt pathways, also promote PD-L1 overexpression ( Zhou et al, 2023 ). Interestingly, a complex interplay between intracellular ROS and PD-L1 expression in cancer cells has recently come to light ( Bailly, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

p66Shc deficiency in CLL cells enhances PD-L1 expression and suppresses immune synapse formation

Lopresti,

Capitani,

Tatangelo

et al. 2024

Front. Cell Dev. Biol.

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Introduction: Escape from immunosurveillance is a hallmark of chronic lymphocytic leukemia (CLL) cells. In the protective niche of lymphoid organs, leukemic cells suppress the ability of T lymphocytes to form the immune synapse (IS), thereby hampering T-cell mediated anti-tumoral activities. By binding its cognate receptor PD-1 at the surface of T lymphocytes, the inhibitory ligand PD-L1, which is overexpressed in CLL cells, mediates the T-cell suppressive activities of CLL cells. However, the molecular mechanism underlying PD-L1 overexpression in CLL cells remains unknown. We have previously reported a defective expression of the pro-apoptotic and pro-oxidant adaptor p66Shc in CLL cells, which is causally related to an impairment in intracellular reactive oxygen species (ROS) production and to the activation of the ROS-sensitive transcription factor NF-κB. The fact that PD-L1 expression is regulated by NF-κB suggests a mechanistic relationship between p66Shc deficiency and PD-L1 overexpression in CLL cells.Methods: 62 treatment-naive CLL patients and 43 healthy donors were included in this study. PD-L1 and p66Shc expression was quantified in B cells by flow cytometry and qRT-PCR. IS architecture and local signaling was assessed by flow cytometry and confocal microscopy. CD8+ cell killing activity was assessed by flow cytometry.Results: Here we show that residual p66Shc expression in leukemic cells isolated both from CLL patients and from the CLL mouse model Eμ-TCL1 inversely correlated with PD-L1 expression. We also show that the PD-L1 increase prevented leukemic cells from forming ISs with T lymphocytes. Reconstitution of p66Shc, but not of a ROS-defective mutant, in both CLL cells and the CLL-derived cell line MEC-1, enhanced intracellular ROS and decreased PD-L1 expression. Similar results were obtained following treatment of CLL cells with H2O2 as exogenous source of ROS, that normalized PD-L1 expression and recovered IS formation.Discussion: Our data provide direct evidence that the p66Shc-deficiency-related ROS depletion in CLL cells concurs to enhance PD-L1 expression and provides a mechanistic basis for the suppression of T cell-mediated anti-tumoral functions in the immunosuppressive lymphoid niche.

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“…Given that the PD-1/PD-L1 pathway has an important role in the generation of an immunosuppressive microenvironment in tumors, there has been a significant interest in examining the regulation mechanisms underpinning the expression of the PD-L1 protein [ 43 , 87 , 88 ]. It seems that there exists a complex network of regulatory processes from epigenetic to post-transcriptional mechanisms which not only control the expression level of PD-L1 but also the resistance to the PD-1/PD-L1 blocking therapies.…”

Section: The Aging-associated Signaling Stimulates the Expression Of ...mentioning

confidence: 99%

The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases

Salminen

2024

J Mol Med

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The accumulation of senescent cells within tissues is a hallmark of the aging process. Senescent cells are also commonly present in many age-related diseases and in the cancer microenvironment. The escape of abnormal cells from immune surveillance indicates that there is some defect in the function of cytotoxic immune cells, e.g., CD8+ T cells and natural killer (NK) cells. Recent studies have revealed that the expression of programmed death-ligand 1 (PD-L1) protein is abundantly increased in senescent cells. An increase in the amount of PD-L1 protein protects senescent cells from clearance by the PD-1 checkpoint receptor in cytotoxic immune cells. In fact, the activation of the PD-1 receptor suppresses the cytotoxic properties of CD8+ T and NK cells, promoting a state of immunosenescence. The inhibitory PD-1/PD-L1 checkpoint pathway acts in cooperation with immunosuppressive cells; for example, activation of PD-1 receptor can enhance the differentiation of regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and M2 macrophages, whereas the cytokines secreted by immunosuppressive cells stimulate the expression of the immunosuppressive PD-L1 protein. Interestingly, many signaling pathways known to promote cellular senescence and the aging process are crucial stimulators of the expression of PD-L1 protein, e.g., epigenetic regulation, inflammatory mediators, mTOR-related signaling, cGAS-STING pathway, and AhR signaling. It seems that the inhibitory PD-1/PD-L1 immune checkpoint axis has a crucial role in the accumulation of senescent cells and thus it promotes the aging process in tissues. Thus, the blockade of the PD-1/PD-L1 checkpoint signaling might be a potential anti-aging senolytic therapy. Key messages Senescent cells accumulate within tissues during aging and age-related diseases. Senescent cells are able to escape immune surveillance by cytotoxic immune cells. Expression of programmed death-ligand 1 (PD-L1) markedly increases in senescent cells. Age-related signaling stimulates the expression of PD-L1 protein in senescent cells. Inhibitory PD-1/PD-L1 checkpoint pathway suppresses clearance of senescent cells.

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PD-L1: expression regulation

Cited by 20 publications

References 243 publications

Construction and validation of a folate metabolism-related gene signature for predicting prognosis in HNSCC

Construction and validation of a folate metabolism-related gene signature for predicting prognosis in HNSCC

p66Shc deficiency in CLL cells enhances PD-L1 expression and suppresses immune synapse formation

The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases

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