Abstract
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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Introduction
Programmed cell death 1 (PD-1) and its ligand PD-L1 have become pivotal in advancing tumor treatment by effectively modulating immune responses [1]. PD-L1 is expressed across various tumors, while PD-1 is primarily expressed on T cells within tumor tissues [2]. PD-L1 engages with PD-1, creating a molecular barrier that inhibits the cytotoxic actions of immune cells [3]. Overcoming this inhibition is possible through blocking antibodies or recombinant proteins that target signaling pathways, reactivating immune responses. Monoclonal antibodies against PD-1 and PD-L1 have demonstrated significant therapeutic success, indicating that immune checkpoint blockade therapy is a potent antitumor treatment. However, its current use mainly as a second-line treatment for advanced tumors and the emergence of drug resistance highlight ongoing challenges [4]. These factors underscore the necessity for continued research to potentially expand its use earlier in treatment protocols.
Exploring new biomarkers and develo** combination drug therapies are essential for combating these challenges. Research has shown that PD-1 transcription can be increased by activating B-cell CLL/lymphoma 6 (BCL6), and various elements, such as cytokines, hypoxia, bromodomain-containing protein 4 (BRD4), and noncoding RNA, can elevate PD-L1 expression by influencing transcription [5, 90].
Glycosylation of PD-L1 affects clinical immunohistochemistry
The glycosylation of PD-L1 can interfere with its detection by immunohistochemical antibodies, potentially causing false-negative results in tests that assess PD-L1 expression in cancer patients. This issue arises when glycosyl structures on the PD-L1 protein prevent antibody binding [90]. To address this issue, researchers have developed a method of removing these sugars—called deglycosylation—before testing. This technique significantly improves the accuracy of PD-L1 detection and correlates better with patients’ responses to anti-PD-1/PD-L1 therapies [182].
Etoposide can inhibit the enzyme STT3, which is involved in N-glycosylation, through its anti-EMT effects, reducing PD-L1 levels and increasing the effectiveness of anti-Tim3 therapy [96]. Clinical trials of etoposide combined with anti-PD-1/PD-L1 immunotherapy are currently underway [183,184,185,186,187,188,189] (Table 2). In a phase III trial for extensive small cell lung cancer, compared with placebo, pembrolizumab combined with etoposide and platinum significantly improved 12-month PFS (13.6% vs. 3.1%, P = 0.0023), enhancing patient quality of life [183, 184]. Another study revealed that atezolizumab combined with carboplatin and etoposide increased overall survival (OS) to 12.3 months from 10.3 months with chemotherapy alone (P = 0.0154) and was well tolerated [185, 186]. Similarly, tislelizumab or serplulimab with the same regimen in different trials extended OS and PFS [188, 189].
Targeting the PD-L1 dimer inhibits PD-L1 function
PD-L1 can form homodimers and tetramers, and its complex glycosylation is linked to the homodimeric structure of its intracellular domain [190]. Natural compounds such as capsaicin, 6-gingerol, and curcumin may block the PD-1/PD-L1 interaction by targeting PD-L1 dimerization, enhancing anticancer immunity [191]. The small molecule BMS-202, with modified carbonyl to hydroxyl groups, produces two enantiomers, MS and MR, both of which disrupt PD-L1 function by targeting its dimerization [192]. Furthermore, compounds such as α-mangostin and ethanol extracts can inhibit PD-L1 glycosylation and promote its degradation by binding within the pocket of the PD-L1 dimer [193]. These findings from preclinical studies highlight the potential of designing inhibitors that target PD-L1 dimers to enhance immunotherapy efficacy.
Treatment prospects and clinical transformation of PD-L1/PD-1 palmitoylation
Palmitoylation of PD-L1 stabilizes the protein, and targeting this modification enhances PD-L1 immunotherapy efficacy. Porcupine, a membrane-bound o-acyltransferase, is targeted by inhibitors such as LGK974, ETC-1,922,159, CGX1321, and RXC004 and is now in phase I trials [194]. These inhibitors have also been tested in combination with anti-PD-1/PD-L1 antibodies in clinical trials (Table 2). Research shows that chloroquine derivatives improve anti-PD-1 therapy in melanoma by targeting palmitoyl protein thioesterase 1 (PPT1) [195]. Combining PPT1 inhibitors with anti-PD-1 antibodies activates T cells, enhancing tumor immunity [196]. Innovative therapies include HHAT and APT1/2 inhibitors and 2-bromopalmitate (2-BP) in polymer-lipid hybrid nanoparticles (2-BP/CPT-PLNs) that replace anti-PD-L1 antibodies in immune checkpoint blockade, showing potent antitumor effects and improved survival in melanoma models [197,198,199]. Additionally, a novel peptide (CPP-S1) that inhibits PD-L1 palmitoylation and promotes its degradation offers another strategy to enhance immunotherapy efficacy [21].
Dai et al. demonstrated that targeting PD-L1 palmitoylation was more effective than direct targeting [200]. Additionally, Shi et al. created a PROTAC (SP-PROTAC) using an anastomotic peptide targeting the palmitoyl transferase ZDHHC3, which significantly reduced PD-L1 expression in a human cervical cancer cell line [201].
ZDHHC9 palmitoylates cGAS at Cys 404/405, enhancing its activation, while depalmitoylation byLYPLAL1 impairs cGAS function. TargetingLYPLAL1-mediated cGAS depalmitoylation could boost cGAS activation and improve antitumor immunotherapy efficacy [202]. As ZDHHC9 also affects PD-L1 palmitoylation, inhibitingLYPLAL1 might enhance overall immunotherapy outcomes.
Therapeutic promise of other PD-L1/PD-1 posttranslational modifications
Several preclinical treatments targeting PD-1/PD-L1 posttranslational modifications are being developed. HDAC2 inhibitors combined with PD-1 antibodies have been shown to significantly delay tumor growth and improve survival in syngeneic MC38 mouse models [22]. JQ-1, which reduces PD-L1 expression through acetylation, shows potential for treating pancreatic cancer [127]. Pevonedistat, a NEDDylation inhibitor, is undergoing clinical trials for various cancers and may upregulate PD-L1 expression, although its effectiveness is still under study [203, 204]. Zhou et al. discovered a UFSP2 inhibitor that enhances UFMyation, decreases PD-L1 expression, and supports PD-1 blockade [59]. CK2 inhibitors trigger PD-L1 autophagic degradation and enhance antitumor immunotherapy when combined with PD-1 antibodies [61]. Additionally, paclitaxel, which increases MMP-13 in certain cancer cells, shows promise for head and neck cancer treatment when used with anti-PD-1 therapy [65]. These methods represent promising strategies for cancer immunotherapy.
Summary and prospective
In this review, we summarize the PTMs of PD-1/PD-L1 and their regulatory mechanisms and propose new targets for biomarkers and combination therapies to enhance PD-1/PD-L1 blockade in immunotherapy. Despite these advances, many aspects of PD-1/PD-L1 PTMs remain elusive. For diagnosis, PD-L1 glycosylation can obscure antibody binding sites, causing false negatives [177]. Additionally, the degradation of the glycan region of the PD-L1 epitope may lead to a loss of staining on immunohistochemistry [205]. The absolute and effective glycosylation levels may also vary significantly [206]. In treatment contexts, PD-L1 PTMs can contribute to tumor progression. In addition to PD-1/PD-L1 blockade, PTMs are vital for antigen presentation, CAR-T-cell therapy, and vaccine development [207]. Innovations such as multifluorescence resonance energy transfer (multi-FRET) are enhancing PTM research, offering new avenues for advancing tumor immunotherapy [208].
Data availability
No datasets were generated or analysed during the current study.
Abbreviations
- 2F‒Fuc:
-
2-fluoro-L-fucose
- ADCC:
-
Antibody-dependent cytotoxicity
- ADPR:
-
ADP-ribose
- ARF9:
-
ADP-ribosylation factor-6
- BC:
-
Breast cancer
- BCL:
-
B-cell lymphoma
- BL:
-
Burkitt lymphoma
- CISH:
-
Cytokine-inducible SH2 domain-containing protein
- CPT:
-
Camptothecin
- CR:
-
Complete response
- CRC:
-
Colorectal cancer
- CSCC:
-
Cutaneous squamous cell carcinoma
- CTLs:
-
Cytotoxic T lymphocytes
- CxCa:
-
Cervical cancer
- Cys or C:
-
Cysteine
- DHHC:
-
Aspartic acid-histidine-histidine-cysteine
- DOR:
-
Duration of response
- ESCC:
-
Esophageal squamous cell carcinoma
- FASN:
-
Fatty acid synthase
- GBM:
-
Glioblastoma
- GC:
-
Gastric cancer
- Gly:
-
Glycine
- HCC:
-
Hepatocellular carcinoma
- HNSCC:
-
Head and neck squamous cell carcinoma
- HRD:
-
Hyperprogressive disease
- ICB:
-
Immune checkpoint blockade
- ICD:
-
Immunogenic cell death
- KATs:
-
Lysine acetylases
- LUAD:
-
Lung adenocarcinoma
- MD:
-
Molecular dynamics
- MHC:
-
Major histocompatibility complex
- MULTI-FRET:
-
Multifluorescence resonance energy transfer
- NPC:
-
Nasopharyngeal carcinoma
- NSCLC:
-
Non-small cell lung cancer
- NSQ:
-
Nonsquamous
- OC:
-
Ovarian cancer
- ORR:
-
Objective response rate
- OS:
-
Overall survival
- OSCC:
-
Oral squamous cell carcinoma
- PC:
-
Prostate cancer
- PCA:
-
pancreatic cancer
- PD-1:
-
Programmed cell death protein 1
- PD-L1:
-
Programmed death-ligand 1
- PDAC:
-
Pancreatic ductal adenocarcinoma
- PFS:
-
Progression-free survival
- PROTACs:
-
PROteolysis-Targeting Chimeras
- PTM:
-
Posttranslational modification
- SCLC:
-
Small cell lung cancer
- SD:
-
Stable disease
- Ser or S:
-
Seronine
- SQ:
-
Squamous
- TCR:
-
T-cell antigen receptor
- Thr or T:
-
Threonine
- TNBC:
-
Triple-negative breast cancer
- TRAE:
-
Treatment-related adverse events
- Tyr or Y:
-
Tyrosine
- ZAP70:
-
ζchain-related tyrosine kinase 70
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Figures were created by PowerPoint (Microsoft Office 2016) and some materials of the figures were provided by the Servier Medical Art (https://smart.servier.com/) under the CC BY 4.0 license.
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This work was supported partially by grants from the National Natural Science Foundation of China (82303069 [J.W.], 52102276 [J.L.], 82303126 [Y.W.]), the Natural Science Foundation of Fujian Province (2023J05038 [J.W.]), the Fujian Provincial Project of Education and Science for Young and Middle-aged Teachers (JAT220076 [J.W.]), the Startup Foundation of Fujian Medical University (2022QH1003 [J.W.], 2022QH1783 [M.C.]), and the Natural Science Foundation of Hunan Province (2024JJ6325 [Y.W.]).
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R.W. and S.H. collected the related paper and finished the manuscript and figures, R.W. and S.H. contributed equally to this work. J.W. and J.L. gave constructive guidance and made critical revisions. Y.W., X.J., M.C. participated in the design of this review. All authors read and approved the final manuscript.
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Wang, R., He, S., Long, J. et al. Emerging therapeutic frontiers in cancer: insights into posttranslational modifications of PD-1/PD-L1 and regulatory pathways. Exp Hematol Oncol 13, 46 (2024). https://doi.org/10.1186/s40164-024-00515-5
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DOI: https://doi.org/10.1186/s40164-024-00515-5