PD-L1 induction via the MEK-JNK-AP1 axis by a neddylation inhibitor promotes cancer-associated immunosuppression

Zhang, Shizhen; You, Xia-Hong; Xu, Tiantian; Chen, Qian; Li, Hua; Dou, Longyu; Sun, Yilun; Xiong, Xiufang; Meredith, Morgan A.; Sun, Yi

doi:10.1038/s41419-022-05292-9

Cited by 18 publications

(15 citation statements)

References 54 publications

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“…It has been reported that inactivation of NAE1 and UBA3 or pevonedistat treatment promoted PD-L1 expression in glioblastoma, lung cancer, and pancreatic cancer cells through c-MYC, ERK1/2, or JNK pathway. 35 , 36 In contrast, pevonedistat did so in ATLL cells through STAT3 activation. Although p-STAT3–driven PD-L1 mRNA expression seems to be a common mechanism among natural killer/T-cell lymphomas cells, ALK + ALCL cells, and ATLL, 11 , 17 , 18 each disease might have a distinct mechanism for STAT3 activation, as illustrated by pevonedistat and ruxolitinib, which affected P-STAT3 in ATLL cells but not in ALK + ALCL cells.…”

Section: Discussionmentioning

confidence: 93%

Whole-genome CRISPR screening identifies molecular mechanisms of PD-L1 expression in adult T-cell leukemia/lymphoma

Chiba,

Shimono,

Suto

et al. 2024

Blood

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Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy with a poor prognosis and limited treatment options. Programmed cell death ligand 1(PD-L1) is recognized to be involved in the pathobiology of ATLL. However, what molecules control PD-L1 expression and whether genetic or pharmacological intervention might modify PD-L1 expression in ATLL cells is still unknown. In order to comprehend the regulatory mechanisms of PD-L1 expression in ATLL cells, we performed unbiased genome-wide clustered regularly interspaced short palindromic repeat (CRISPR) screening in this work. In ATLL cells, we discovered that the neddylation-associated genes NEDD8, NAE1, UBA3, and CUL3 negatively regulated PD-L1 expression while STAT3 positively did so in ATLL cells. We verified, in line with the genetic results, that treatment with the JAK1/2 inhibitor ruxolitinib or the neddylation pathway inhibitor pevonedistat resulted in a decrease in PD-L1 expression in ATLL cells or an increase in it. It is significant that these results held true regardless of whether ATLL cells had the PD-L1 3' structural variant, a known genetic anomaly that promotes PD-L1 overexpression in certain primary ATLL patients. Pevonedistat alone showed cytotoxicity for ATLL cells, but compared to each single modality, pevonedistat improved the cytotoxic effects of the anti-PD-L1 monoclonal antibody Avelumab and chimeric antigen receptor T-cells targeting PD-L1 in vitro. As a result, our work provided insight into a portion of the complex regulatory mechanisms governing PD-L1 expression in ATLL cells and demonstrated the in vitro preliminary preclinical efficacy of PD-L1-directed immunotherapies by using pevonedistat to upregulate PD-L1 in ATLL cells.

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Section: Discussionmentioning

confidence: 93%

Whole-genome CRISPR screening identifies molecular mechanisms of PD-L1 expression in adult T-cell leukemia/lymphoma

Chiba,

Shimono,

Suto

et al. 2024

Blood

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“…Pevonedistat (MLN4924, TAK924) is a small molecule inhibitor of NEDD8. Pevonedistat blocks the degradation of the PD-L1 protein by inhibiting Cullin3 activity [ 64 , 65 ], increasing the levels of PD-L1 mRNA and protein in a dose- and time-dependent manner [ 66 ]. (Fig.…”

Section: Preclinical Study Of Ptms Inhibiting Pd-l1 Expression and Fu...mentioning

confidence: 99%

Emerging therapeutic frontiers in cancer: insights into posttranslational modifications of PD-1/PD-L1 and regulatory pathways

Wang,

He,

Long

et al. 2024

Exp Hematol Oncol

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The interaction between programmed cell death ligand 1 (PD-L1), which is expressed on the surface of tumor cells, and programmed cell death 1 (PD-1), which is expressed on T cells, impedes the effective activation of tumor antigen-specific T cells, resulting in the evasion of tumor cells from immune-mediated killing. Blocking the PD-1/PD-L1 signaling pathway has been shown to be effective in preventing tumor immune evasion. PD-1/PD-L1 blocking antibodies have garnered significant attention in recent years within the field of tumor treatments, given the aforementioned mechanism. Furthermore, clinical research has substantiated the efficacy and safety of this immunotherapy across various tumors, offering renewed optimism for patients. However, challenges persist in anti-PD-1/PD-L1 therapies, marked by limited indications and the emergence of drug resistance. Consequently, identifying additional regulatory pathways and molecules associated with PD-1/PD-L1 and implementing judicious combined treatments are imperative for addressing the intricacies of tumor immune mechanisms. This review briefly outlines the structure of the PD-1/PD-L1 molecule, emphasizing the posttranslational modification regulatory mechanisms and related targets. Additionally, a comprehensive overview on the clinical research landscape concerning PD-1/PD-L1 post-translational modifications combined with PD-1/PD-L1 blocking antibodies to enhance outcomes for a broader spectrum of patients is presented based on foundational research.

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“…Beyond its anticipated therapeutic effects in targeted therapy, MLN4924 has demonstrated certain unintended consequences that may foster cancer cell proliferation. These outcomes are primarily associated with the activation of intracellular ERK and JNK signaling, leading to activator protein-1 activation ( 133 ). Simultaneously, the inhibitory effects of MLN4924-induced neddylation suppression can upregulate T-cell negative regulator programmed death-ligand 1 (PD-L1) expression ( 134 ).…”

Section: Exploration Of Neddylation As a Potential Molecularly Target...mentioning

confidence: 99%

“…Cancer cells exhibiting a high expression of PD-L1 can attenuate T-cell cytotoxicity through the activation of the PD-1/PD-L1 axis, inducing immune suppression ( 135 ). Combining anti-PD-L1 antibodies or mitogen-activated protein kinase inhibitors with MLN4924 administration offers a potential avenue to address these challenges effectively ( 133 ).…”

Section: Exploration Of Neddylation As a Potential Molecularly Target...mentioning

confidence: 99%

Advancements in colorectal cancer research: Unveiling the cellular and molecular mechanisms of neddylation (Review)

Wang,

Li,

et al. 2024

Int J Oncol

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Neddylation, akin to ubiquitination, represents a post-translational modification of proteins wherein neural precursor cell-expressed developmentally downregulated protein 8 (NEDD8) is modified on the substrate protein through a series of reactions. Neddylation plays a pivotal role in the growth and proliferation of animal cells. In colorectal cancer (CRC), it predominantly contributes to the proliferation, metastasis and survival of tumor cells, decreasing overall patient survival. The strategic manipulation of the NEDD8-mediated neddylation pathway holds immense therapeutic promise in terms of the potential to modulate the growth of tumors by regulating diverse biological responses within cancer cells, such as DNA damage response and apoptosis, among others. MLN4924 is an inhibitor of NEDD8, and its combined use with platinum drugs and irinotecan, as well as cycle inhibitors and NEDD activating enzyme inhibitors screened by drug repurposing, has been found to exert promising antitumor effects. The present review summarizes the recent progress made in the understanding of the role of NEDD8 in the advancement of CRC, suggesting that NEDD8 is a promising anti-CRC target.

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PD-L1 induction via the MEK-JNK-AP1 axis by a neddylation inhibitor promotes cancer-associated immunosuppression

Cited by 18 publications

References 54 publications

Whole-genome CRISPR screening identifies molecular mechanisms of PD-L1 expression in adult T-cell leukemia/lymphoma

Whole-genome CRISPR screening identifies molecular mechanisms of PD-L1 expression in adult T-cell leukemia/lymphoma

Emerging therapeutic frontiers in cancer: insights into posttranslational modifications of PD-1/PD-L1 and regulatory pathways

Advancements in colorectal cancer research: Unveiling the cellular and molecular mechanisms of neddylation (Review)

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