PD-L1 translocation to the plasma membrane enables tumor immune evasion through MIB2 ubiquitination

Yu, Xinfang; Li, Wei; Liu, Haidan; Wang, Xu; Coarfa, Cristian; Cheng, Chao; Yu, Xinlian; Zeng, Zhaoyang; Cao, Yang; Young, Ken H.; Li, Yong

doi:10.1172/jci160456

Cited by 16 publications

(13 citation statements)

References 64 publications

(73 reference statements)

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“…Ding’s team found that sodium-glucose cotransporter 2 (SGLT2) colocalizes with PD-L1 in the cell membrane and circulating endosomes, preventing proteasome-mediated PD-L1 degradation [ 48 ]. Yu et al discovered that MIB E3 ubiquitin protein ligase 2 (MIB2) catalyzes the nonproteolytic K63-linked polyubiquitination of PD-L1, facilitating its transport of PD-L1 from the trans-Golgi network (TGN) to the membrane through RAS-associated binding 8-mediated (RAB8-mediated) exocytosis [ 49 ]. (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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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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“…On the one hand, newly synthesized PD-L1 is transported from the Golgi apparatus to membrane. [53] On the other hand, mPD-L1 conducts a series of measures to save itself from degradation. Post-transnational modifications involving ubiquitination, acetylation, and palmitoylation reactions can control mPD-L1's stability and transcriptional activity.…”

Section: Mechanisms For Up-regulation Of Mpd-l1mentioning

confidence: 99%

“…During the whole process, synthesized PD-L1 in the cytosol is transported to the membrane to restore the mPD-L1 pool, thus promoting immune evasion. [53,54] Specifically, newly synthesized PD-L1 is added with k63-linked ubiquitination under the control of mind bomb homolog 2 (MIB2), a type of E3 ligase. Then ubiquitinated PD-L1 translocates from Golgi to the membrane by Ras-associated binding 8-mediated (RAB8-mediated) exocytosis.…”

Section: Mechanisms For Up-regulation Of Mpd-l1mentioning

confidence: 99%

“…Then ubiquitinated PD-L1 translocates from Golgi to the membrane by Ras-associated binding 8-mediated (RAB8-mediated) exocytosis. [53] However, little is known about the mechanism driving PD-L1 translocation to the plasma membrane after de novo synthesis. More efforts should be directed toward the mechanism of de novo synthesis.…”

Section: Mechanisms For Up-regulation Of Mpd-l1mentioning

confidence: 99%

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Challenges Coexist with Opportunities: Spatial Heterogeneity Expression of PD‐L1 in Cancer Therapy

Wang,

Zhou,

Yang

et al. 2023

Advanced Science

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Cancer immunotherapy using anti‐programmed death‐ligand 1 (PD‐L1) antibodies has been used in various clinical applications and achieved certain results. However, such limitations as autoimmunity, tumor hyperprogression, and overall low patient response rate impede its further clinical application. Mounting evidence has revealed that PD‐L1 is not only present in tumor cell membrane but also in cytoplasm, exosome, or even nucleus. Among these, the dynamic and spatial heterogeneous expression of PD‐L1 in tumors is mainly responsible for the unsatisfactory efficacy of PD‐L1 antibodies. Hence, numerous studies focus on inhibiting or degrading PD‐L1 to improve immune response, while a comprehensive understanding of the molecular mechanisms underlying spatial heterogeneity of PD‐L1 can fundamentally transform the current status of PD‐L1 antibodies in clinical development. Herein, the concept of spatial heterogeneous expression of PD‐L1 is creatively introduced, encompassing the structure and biological functions of various kinds of PD‐L1 (including mPD‐L1, cPD‐L1, nPD‐L1, and exoPD‐L1). Then an in‐depth analysis of the regulatory mechanisms and potential therapeutic targets of PD‐L1 is provided, seeking to offer a solid basis for future investigation. Moreover, the current status of agents is summarized, especially small molecular modulators development directed at these new targets, offering a novel perspective on potential PD‐L1 therapeutics strategies.

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“…PD-L1 tends to internalize after the binding of antibody, during which some of it is lysosome-mediated degradation 8 . However, most of the internalized PD-L1 can be stored in recycling endosomes and repopulated to the cell membrane 9 , mediating resistance to ICI treatment targeting PD-L1 10 , 11 . Therefore, promoting lysosomal degradation and inhibiting the recycling of PD-L1 is a promising approach to overcome the resistance to ICI therapy 12 .…”

Section: Introductionmentioning

confidence: 99%

Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation

Xu,

Xie,

Zhou

et al. 2024

Nat Commun

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Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway has become a powerful clinical strategy for treating cancer, but its efficacy is complicated by various resistance mechanisms. One of the reasons for the resistance is the internalization and recycling of PD-L1 itself upon antibody binding. The inhibition of lysosome-mediated degradation of PD-L1 is critical for preserving the amount of PD-L1 recycling back to the cell membrane. In this study, we find that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway and reduces PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding which inhibits the CMTM6-PD-L1 interaction. We further identify an Hsp90α/β inhibitor, AUY-922, which induces Hsc70 expression and PD-L1 lysosomal degradation. Either Hsc70 overexpression or AUY-922 treatment can reduce PD-L1 expression, inhibit tumor growth and promote anti-tumor immunity in female mice; AUY-922 can further enhance the anti-tumor efficacy of anti-PD-L1 and anti-CTLA4 treatment. Our study elucidates a molecular mechanism of Hsc70-mediated PD-L1 lysosomal degradation and provides a target and therapeutic strategies for tumor immunotherapy.

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PD-L1 translocation to the plasma membrane enables tumor immune evasion through MIB2 ubiquitination

Cited by 16 publications

References 64 publications

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

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

Challenges Coexist with Opportunities: Spatial Heterogeneity Expression of PD‐L1 in Cancer Therapy

Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation

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