Full Text:   <110>

Summary:  <11>

CLC number: 

On-line Access: 2022-10-12

Received: 2022-04-04

Revision Accepted: 2022-07-13

Crosschecked: 2022-10-13

Cited: 0

Clicked: 221

Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Ai-fu Lin

https://orcid.org/0000-0002-3968-3617

-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2022 Vol.23 No.10 P.823-843

http://doi.org/10.1631/jzus.B2200195


Tumor immune checkpoints and their associated inhibitors


Author(s):  Zerui GAO, Xingyi LING, Chengyu SHI, Ying WANG, Aifu LIN

Affiliation(s):  MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China; more

Corresponding email(s):   linaifu@zju.edu.cn

Key Words:  Immune checkpoint, Immune checkpoint inhibitor, Programmed cell death-ligand 1 (PD-L1), Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), Lymphocyte activation gene-3 (LAG-3), T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), B7 family


Zerui GAO, Xingyi LING, Chengyu SHI, Ying WANG, Aifu LIN. Tumor immune checkpoints and their associated inhibitors[J]. Journal of Zhejiang University Science B, 2022, 23(10): 823-843.

@article{title="Tumor immune checkpoints and their associated inhibitors",
author="Zerui GAO, Xingyi LING, Chengyu SHI, Ying WANG, Aifu LIN",
journal="Journal of Zhejiang University Science B",
volume="23",
number="10",
pages="823-843",
year="2022",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2200195"
}

%0 Journal Article
%T Tumor immune checkpoints and their associated inhibitors
%A Zerui GAO
%A Xingyi LING
%A Chengyu SHI
%A Ying WANG
%A Aifu LIN
%J Journal of Zhejiang University SCIENCE B
%V 23
%N 10
%P 823-843
%@ 1673-1581
%D 2022
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2200195

TY - JOUR
T1 - Tumor immune checkpoints and their associated inhibitors
A1 - Zerui GAO
A1 - Xingyi LING
A1 - Chengyu SHI
A1 - Ying WANG
A1 - Aifu LIN
J0 - Journal of Zhejiang University Science B
VL - 23
IS - 10
SP - 823
EP - 843
%@ 1673-1581
Y1 - 2022
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2200195


Abstract: 
Immunological evasion is one of the defining characteristics of cancers, as the immune modification of an immune checkpoint (IC) confers immune evasion capabilities to tumor cells. Multiple ICs, such as programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), can bind to their respective receptors and reduce tumor immunity in a variety of ways, including blocking immune cell activation signals. IC blockade (ICB) therapies targeting these checkpoint molecules have demonstrated significant clinical benefits. This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers. Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment. In this review, we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels, including epigenetic regulation, transcriptional regulation, and post-translational modifications. In addition, we provide a summary of the medications targeting various nodes in the regulatory pathway, and highlight the potential of newly identified IC molecules, focusing on their potential implications for cancer diagnostics and immunotherapy.

肿瘤免疫检查点及与其相关抑制剂

高泽瑞1,2,3,4,凌幸怡1,2,3,石成瑜1,2,3,王颖1,2,3,林爱福1,2,3,5,6,7
1浙江大学生命科学学院生命系统稳态与保护教育部重点实验室,中国杭州市,310058
2浙江大学癌症研究中心,中国杭州市,310058
3浙江省细胞与基因工程重点实验室,中国杭州市,310058
4浙江大学竺可桢荣誉学院,中国杭州市,310058
5浙江大学医学院附属第一医院乳腺疾病诊治中心,中国杭州市,310058
6浙江大学医学院第四附属医院国际医学院,中国义乌市,322000
7浙江大学-齐鲁制药联合研究院,中国杭州市,310058
概要:包括程序性细胞死亡蛋白1(PD-1)和细胞毒性T淋巴细胞相关抗原4(CTLA-4)在内的免疫检查点蛋白,可以与各自的受体结合,以阻断免疫细胞的激活信号等方式促进肿瘤细胞免疫逃逸。这种由免疫检查点的免疫修饰赋予的肿瘤细胞免疫规避能力,使得免疫逃逸成为肿瘤的重要特征之一。靶向上述分子的免疫检查点阻断(ICB)疗法通过抗体与特定小分子抑制剂抑制肿瘤关键信号通路,破解肿瘤患者的免疫耐受,已表现出优异的临床效益。因此,破译这些免疫检查点分子的作用和调节机制将为临床治疗提供关键的理论指导。在这篇综述中,我们总结了目前关于这些免疫检查点分子在多个层面上的功能和调节机制,包括表观遗传调节、转录调节和翻译后修饰。此外,我们还对针对调控途径中各个节点的药物进行了总结,进一步阐明新鉴定的免疫检查点分子的临床潜力,重点介绍了它们对癌症诊断和免疫治疗的潜在意义。

关键词:免疫检查点;免疫检查点抑制剂;PD-L1;CTLA-4;LAG-3;TIGIT;B7家族

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1]AgataY, KawasakiA, NishimuraH, et al., 1996. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol, 8(5):765-772.

[2]AhnHK, KimS, KwonD, et al., 2019. MET receptor tyrosine kinase regulates the expression of co-stimulatory and co-inhibitory molecules in tumor cells and contributes to PD-L1-mediated suppression of immune cell function. Int J Mol Sci, 20(17):4287.

[3]AkbayEA, KoyamaS, CarreteroJ, et al., 2013. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov, 3(12):‍1355-1363.

[4]AlbitarM, SudarsanamS, MaWL, et al., 2018. Correlation of MET gene amplification and TP53 mutation with PD-L1 expression in non-small cell lung cancer. Oncotarget, 9(17):13682-13693.

[5]AlegreML, NoelPJ, EisfelderBJ, et al., 1996. Regulation of surface and intracellular expression of CTLA4 on mouse T cells. J Immunol, 157(11):4762-4770.

[6]al EmranA, ChatterjeeA, RodgerEJ, et al., 2019. Targeting DNA methylation and EZH2 activity to overcome melanoma resistance to immunotherapy. Trends Immunol, 40(4):328-344.

[7]AnastasiadouE, StroopinskyD, AlimpertiS, et al., 2019. Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas. Leukemia, 33(1):132-147.

[8]AndersonAC, JollerN, KuchrooVK, 2016. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity, 44(5):989-1004.

[9]AshizawaM, OkayamaH, IshigameT, et al., 2019. miRNA-148a-3p regulates immunosuppression in DNA mismatch repair-deficient colorectal cancer by targeting PD-L1. Mol Cancer Res, 17(6):1403-1413.

[10]AtsavesV, TsesmetzisN, ChioureasD, et al., 2017. PD-L1 is commonly expressed and transcriptionally regulated by STAT3 and MYC in ALK-negative anaplastic large-cell lymphoma. Leukemia, 31(7):1633-1637.

[11]BaixerasE, HuardB, MiossecC, et al., 1992. Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens. J Exp Med, 176(2):327-337.

[12]BarsoumIB, SmallwoodCA, SiemensDR, et al., 2014. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res, 74(3):665-674.

[13]BaumeisterSH, FreemanGJ, DranoffG, et al., 2016. Coinhibitory pathways in immunotherapy for cancer. Annu Rev Immunol, 34:539-573.

[14]BorstJ, BusselaarJ, BosmaDMT, et al., 2021. Mechanism of action of PD-1 receptor/ligand targeted cancer immunotherapy. Eur J Immunol, 51(8):1911-1920.

[15]BoussiotisVA, 2016. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med, 375(18):1767-1778.

[16]BuLL, YuGT, WuL, et al., 2017. STAT3 induces immunosuppression by upregulating PD-1/PD-L1 in HNSCC. J Dent Res, 96(9):1027-1034.

[17]BuissonS, TriebelF, 2005. LAG-3 (CD223) reduces macrophage and dendritic cell differentiation from monocyte precursors. Immunology, 114(3):369-374.

[18]BurrML, SparbierCE, ChanYC, et al., 2017. CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity. Nature, 549(7670):101-105.

[19]ButteMJ, KeirME, PhamduyTB, et al., 2007. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity, 27(1):111-122.

[20]CaseySC, TongL, LiYL, et al., 2016. MYC regulates the antitumor immune response through CD47 and PD-L1. Science, 352(6282):227-231.

[21]CastellanosJR, PurvisIJ, LabakCM, et al., 2017. B7-H3 role in the immune landscape of cancer. Am J Clin Exp Immunol, 6(4):66-75.

[22]CeerazS, NowakEC, NoelleRJ, 2013. B7 family checkpoint regulators in immune regulation and disease. Trends Immunol, 34(11):556-563.

[23]CerezoM, GuemiriR, DruillennecS, et al., 2018. Translational control of tumor immune escape via the eIF4F-STAT1-PD-L1 axis in melanoma. Nat Med, 24(12):‍1877-1886.

[24]CesanoA, WarrenS, 2018. Bringing the next generation of immuno-oncology biomarkers to the clinic. Biomedicines, 6:14.

[25]ChaJH, YangWH, XiaWY, et al., 2018. Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of PD-L1. Mol Cell, 71(4):606-620.E7.

[26]ChanLC, LiCW, XiaWY, et al., 2019. IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion. J Clin Invest, 129(8):3324-3338.

[27]ChangLC, ChenTP, KuoWK, et al., 2018. The protein expression of PDL1 is highly correlated with those of eIF2α and ATF4 in lung cancer. Dis Markers, 2018:5068701.

[28]ChangRM, XiaoS, LeiX, et al., 2017. miRNA-487a promotes proliferation and metastasis in hepatocellular carcinoma. Clin Cancer Res, 23(10):2593-2604.

[29]ChapovalAI, NiJ, LauJS, et al., 2001. B7-H3: a costimulatory molecule for T cell activation and IFN-γ production. Nat Immunol, 2(3):269-274.

[30]ChauvinJM, PaglianoO, FourcadeJ, et al., 2015. TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J Clin Invest, 125(5):2046-2058.

[31]ChenBJ, ChapuyB, OuyangJ, et al., 2013. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res, 19(13):3462-3473.

[32]ChenC, LiuJM, LuoYP, 2020, MicroRNAs in tumor immunity: functional regulation in tumor-associated macrophages. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(1):12-28.

[33]ChenLM, GibbonsDL, GoswamiS, et al., 2014. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun, 5:5241.

[34]ChenMX, PockajB, AndreozziM, et al., 2018. JAK2 and PD-L1 amplification enhance the dynamic expression of PD-L1 in triple-negative breast cancer. Clin Breast Cancer, 18(5):E1205-E1215.

[35]ChengHY, BorczukA, JanakiramM, et al., 2018. Wide expression and significance of alternative immune checkpoint molecules, B7x and HHLA2, in PD-L1-negative human lung cancers. Clin Cancer Res, 24(8):‍1954-1964.

[36]ChengPY, EksiogluEA, ChenXH, et al., 2019. S100A9-induced overexpression of PD-1/PD-L1 contributes to ineffective hematopoiesis in myelodysplastic syndromes. Leukemia, 33(8):2034-2046.

[37]ClarkeJM, GeorgeDJ, LisiS, et al., 2018. Immune checkpoint blockade: the new frontier in cancer treatment. Targ Oncol, 13(1):1-20.

[38]CoelhoMA, de Carné TrécessonS, RanaS, et al., 2017. Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA. Immunity, 47(6):‍1083-1099.e6.

[39]DaiXM, BuX, GaoY, et al., 2021. Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade. Mol Cell, 81(11):‍2317-2331.e6.

[40]DangajD, LanitisE, ZhaoAZ, et al., 2013. Novel recombinant human B7-H4 antibodies overcome tumoral immune escape to potentiate T-cell antitumor responses. Cancer Res, 73(15):4820-4829.

[41]D'ArrigoP, RussoM, ReaA, et al., 2017. A regulatory role for the co-chaperone FKBP51s in PD-L1 expression in glioma. Oncotarget, 8(40):68291-68304.

[42]DarvinP, NairVS, ElkordE, 2019. PD-L1 expression in human breast cancer stem cells is epigenetically regulated through posttranslational histone modifications. J Oncol, 2019:3958908.

[43]DavidJM, DominguezC, MccampbellKK, et al., 2017. A novel bifunctional anti-PD-L1/TGF-‍βtrap fusion protein (M7824) efficiently reverts mesenchymalization of human lung cancer cells. Oncoimmunology, 6(10):e1349589.

[44]DemuthC, AndersenMN, JakobsenKR, et al., 2017. Increased PD-L1 expression in erlotinib-resistant NSCLC cells with MET gene amplification is reversed upon MET-TKI treatment. Oncotarget, 8(40):68221-68229.

[45]de VosL, GrünwaldI, BawdenEG, et al., 2020. The landscape of CD28, CD80, CD86, CTLA4, and ICOS DNA methylation in head and neck squamous cell carcinomas. Epigenetics, 15(11):1195-1212.

[46]DorandRD, NthaleJ, MyersJT, et al., 2016. Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity. Science, 353(6297):399-403.

[47]DuLY, LeeJH, JiangHF, et al., 2020. β-Catenin induces transcriptional expression of PD-L1 to promote glioblastoma immune evasion. J Exp Med, 217(11):e20191115.

[48]EmaldiM, Nunes-XavierCE, 2022. B7-H4 immune checkpoint protein affects viability and targeted therapy of renal cancer cells. Cells, 11(9):1448.

[49]FiedlerM, SchulzD, PiendlG, et al., 2020. Buparlisib modulates PD-L1 expression in head and neck squamous cell carcinoma cell lines. Exp Cell Res, 396(1):112259.

[50]Flem-KarlsenK, FodstadØ, Nunes-XavierCE, 2020. B7-H3 immune checkpoint protein in human cancer. Curr Med Chem, 27(24):4062-4086.

[51]FliesDB, WangSD, XuHY, et al., 2011. Cutting edge: a monoclonal antibody specific for the programmed death-1 homolog prevents graft-versus-host disease in mouse models. J Immunol, 187(4):1537-1541.

[52]FranzenA, VogtTJ, MüllerT, et al., 2018. PD-L1 (CD274) and PD-L2 (PDCD1LG2) promoter methylation is associated with HPV infection and transcriptional repression in head and neck squamous cell carcinomas. Oncotarget, 9(1):641-650.

[53]FuhrmanCA, YehWI, SeayHR, et al., 2015. Divergent phenotypes of human regulatory T cells expressing the receptors TIGIT and CD226. J Immunol, 195(1):145-155.

[54]GainorJF, ShawAT, SequistLV, et al., 2016. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis. Clin Cancer Res, 22(18):4585-4593.

[55]GaoL, XiaLL, JiWX, et al., 2021. Knockdown of CDK5 down-regulates PD-L1 via the ubiquitination-proteasome pathway and improves antitumor immunity in lung adenocarcinoma. Transl Oncol, 14(9):101148.

[56]GaoY, NihiraNT, BuX, et al., 2020. Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy. Nat Cell Biol, 22(9):1064-1075.

[57]Garcia-DiazA, ShinDS, MorenoBH, et al., 2017. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep, 19(6):1189-1201.

[58]GibsonHM, HedgcockCJ, AufieroBM, et al., 2007. Induction of the CTLA-4 gene in human lymphocytes is dependent on NFAT binding the proximal promoter. J Immunol, 179(6):3831-3840.

[59]GoltzD, GevenslebenH, DietrichJ, et al., 2017. PD-L1 (CD274) promoter methylation predicts survival in colorectal cancer patients. Oncoimmunology, 6(1):e1257454.

[60]GoltzD, GevenslebenH, VogtTJ, et al., 2018. CTLA4 methylation predicts response to anti-PD-1 and anti-CTLA-4 immunotherapy in melanoma patients. JCI Insight, 3(13):e96793.

[61]GreenMR, RodigS, JuszczynskiP, et al., 2012. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res, 18(6):1611-1618.

[62]GreenwaldRJ, FreemanGJ, SharpeAH, 2005. The B7 family revisited. Annu Rev Immunol, 23:515-548.

[63]GrosA, RobbinsPF, YaoX, et al., 2014. PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors. J Clin Invest, 124(5):2246-2259.

[64]GuoW, TanFW, HuaiQL, et al., 2021. Comprehensive analysis of PD-L1 expression, immune infiltrates, and m6A RNA methylation regulators in esophageal squamous cell carcinoma. Front Immunol, 12:669750.

[65]HarjunpääH, GuillereyC, 2020. TIGIT as an emerging immune checkpoint. Clin Exp Immunol, 200(2):108-119.

[66]HegdePS, ChenDS, 2020. Top 10 challenges in cancer immunotherapy. Immunity, 52(1):17-35.

[67]HouJW, ZhaoRC, XiaWY, et al., 2020. PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis. Nat Cell Biol, 22(10):1264-1275.

[68]HoweFS, FischlH, MurraySC, et al., 2017. Is H3K4me3 instructive for transcription activation? BioEssays, 39(1):1-12.

[69]HsuJM, XiaWY, HsuYH, et al., 2018. STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion. Nat Commun, 9:1908.

[70]HuangKCY, ChiangSF, ChenWTL, et al., 2020. Decitabine augments chemotherapy-induced PD-L1 upregulation for PD-L1 blockade in colorectal cancer. Cancers, 12(2):462.

[71]HuangSF, BaiXF, FangTY, et al., 2021. Gastrointestinal toxicities associated with immune checkpoint inhibitors: a disproportionality analysis leveraging VigiBase, the WHO Adverse Drug Reaction Database. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 22(2):156-164.

[72]HuardB, TournierM, HercendT, et al., 1994. Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T-lymphocytes. Eur J Immunol, 24(12):3216-3221.

[73]IkedaS, OkamotoT, OkanoS, et al., 2016. PD-L1 is upregulated by simultaneous amplification of the PD-L1 and JAK2 genes in non-small cell lung cancer. J Thorac Oncol, 11(1):62-71.

[74]IñarrairaeguiM, MeleroI, SangroB, 2018. Immunotherapy of hepatocellular carcinoma: facts and hopes. Clin Cancer Res, 24(7):1518-1524.

[75]JanakiramM, ChinaiJM, FinebergS, et al., 2015. Expression, clinical significance, and receptor identification of the newest B7 family member HHLA2 protein. Clin Cancer Res, 21(10):2359-2366.

[76]JebbawiF, Fayyad-KazanH, MerimiM, et al., 2014. A microRNA profile of human CD8+ regulatory T cells and characterization of the effects of microRNAs on Treg cell-associated genes. J Transl Med, 12:218.

[77]JiaL, XiQ, WangHF, et al., 2017. miR-142-5p regulates tumor cell PD-L1 expression and enhances anti-tumor immunity. Biochem Biophys Res Commun, 488(2):425-431.

[78]JiangXF, ZhouJ, Giobbie-HurderA, et al., 2013. The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3K inhibition. Clin Cancer Res, 19(3):‍‍598-609.

[79]JiangXG, 2020. Lymphatic vasculature in tumor metastasis and immunobiology. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(1):3-11.

[80]JiaoSP, XiaWY, YamaguchiH, et al., 2017. PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res, 23(14):3711-3720.

[81]JohnstonRJ, Comps-AgrarL, HackneyJ, et al., 2014. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell, 26(6):‍923-937.

[82]KimEY, KimA, KimSK, et al., 2017. MYC expression correlates with PD-L1 expression in non-small cell lung cancer. Lung Cancer, 110:63-67.

[83]KleinO, KeeD, MarkmanB, et al., 2021. Evaluation of TMB as a predictive biomarker in patients with solid cancers treated with anti-PD-1/CTLA-4 combination immunotherapy. Cancer Cell, 39(5):592-593.

[84]KohJ, JangJY, KeamB, et al., 2016. EML4-ALK enhances programmed cell death-ligand 1 expression in pulmonary adenocarcinoma via hypoxia-inducible factor (HIF)‍-1αand STAT3. Oncoimmunology, 5(3):e1108514.

[85]KormanAJ, PeggsKS, AllisonJP, 2006. Checkpoint blockade in cancer immunotherapy. Adv Immunol, 90: 297-339.

[86]KouoT, HuangLQ, PucsekAB, et al., 2015. Galectin-3 shapes antitumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells. Cancer Immunol Res, 3(4):412-423.

[87]KourepiniE, PaschalidisN, SimoesDCM, et al., 2016. TIGIT enhances antigen-specific Th2 recall responses and allergic disease. J Immunol, 196(9):3570-3580.

[88]KurtulusS, SakuishiK, NgiowSF, et al., 2015. TIGIT predominantly regulates the immune response via regulatory T cells. J Clin Invest, 125(11):4053-4062.

[89]LamanoJB, LamanoJB, LiYD, et al., 2019. Glioblastoma-derived IL6 induces immunosuppressive peripheral myeloid cell PD-L1 and promotes tumor growth. Clin Cancer Res, 25(12):3643-3657.

[90]LastwikaKJ, WilsonIII W, LiQK, et al., 2016. Control of PD-L1 expression by oncogenic activation of the AKT-mTOR pathway in non-small cell lung cancer. Cancer Res, 76(2):227-238.

[91]LeeYH, Martin-OrozcoN, ZhengPL, et al., 2017. Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function. Cell Res, 27(8):1034-1045.

[92]LeitnerJ, KlauserC, PicklWF, et al., 2009. B7-H3 is a potent inhibitor of human T-cell activation: no evidence for B7-H3 and TREML2 interaction. Eur J Immunol, 39(7):1754-1764.

[93]LeongSR, LiangWC, WuY, et al., 2015. An anti-B7-H4 antibody-drug conjugate for the treatment of breast cancer. Mol Pharm, 12(6):1717-1729.

[94]LiCW, LimSO, XiaWY, et al., 2016. Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity. Nat Commun, 7:12632.

[95]LiCW, LimSO, ChungEM, et al., 2018. Eradication of triple-negative breast cancer cells by targeting glycosylated PD-L1. Cancer Cell, 33(2):187-201.e10.

[96]LiFY, ZhaoX, ZhangYL, et al., 2021. TFH cells depend on Tcf1-intrinsic HDAC activity to suppress CTLA4 and guard B-cell help function. Proc Natl Acad Sci USA, 118(2):e2014562118.

[97]LiH, LiCW, LiXQ, et al., 2019. Met inhibitors promote liver tumor evasion of the immune response by stabilizing PDL1. Gastroenterology, 156(6):1849-1861.e13.

[98]LiM, XiaPY, DuY, et al., 2014. T-cell immunoglobulin and ITIM domain (TIGIT) receptor/poliovirus receptor (PVR) ligand engagement suppresses interferon-‍γproduction of natural killer cells viaβ‍-arrestin 2-mediated negative signaling. J Biol Chem, 289(25):17647-17657.

[99]LiangMQ, YuFQ, ChenC, 2020. C-Myc regulates PD-L1 expression in esophageal squamous cell carcinoma. Am J Transl Res, 12(2):379-388.

[100]LimSO, LiCW, XiaWY, et al., 2016. Deubiquitination and stabilization of PD-L1 by CSN5. Cancer Cell, 30(6):‍925-939.

[101]LimTS, ChewV, SieowJL, et al., 2016. PD-1 expression on dendritic cells suppresses CD8+ T cell function and antitumor immunity. Oncoimmunology, 5(3):e1085146.

[102]LinsleyPS, BradshawJ, GreeneJ, et al., 1996. Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. Immunity, 4(6):535-543.

[103]LiuJ, YuanY, ChenWN, et al., 2015. Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses. Proc Natl Acad Sci USA, 112(21):6682-6687.

[104]LuCW, PaschallAV, ShiHD, et al., 2017. The MLL1-H3K4me3 axis-mediated PD-L1 expression and pancreatic cancer immune evasion. J Natl Cancer Inst, 109(6):djw283.

[105]LuanXY, YuWZ, CaoQZ, et al., 2009. The effects of B7H4 on human bone marrow mesenchymal stem cell inhibiting proliferation of PHA activated T cells. Chin J Hematol, 30(10):689-693 (in Chinese).

[106]MaherCM, ThomasJD, HaasDA, et al., 2018. Small-molecule Sigma1 modulator induces autophagic degradation of PD-L1. Mol Cancer Res, 16(2):243-255.

[107]MahnkeK, RingS, JohnsonTS, et al., 2007. Induction of immunosuppressive functions of dendritic cells in vivo by CD4+CD25+ regulatory T cells: role of B7-H3 expression and antigen presentation. Eur J Immunol, 37(8):2117-2126.

[108]MaoXB, OuMT, KaruppagounderSS, et al., 2016. Pathological α‍-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science, 353(6307):eaah3374.

[109]MarwitzS, ScheufeleS, PernerS, et al., 2017. Epigenetic modifications of the immune-checkpoint genes CTLA4 and PDCD1 in non-small cell lung cancer results in increased expression. Clin Epigenetics, 9:51.

[110]MarzecM, ZhangQ, GoradiaA, et al., 2008. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc Natl Acad Sci USA, 105(52):20852-20857.

[111]MeadKI, ZhengY, ManzottiCN, et al., 2005. Exocytosis of CTLA-4 is dependent on phospholipase D and ADP ribosylation factor-1 and stimulated during activation of regulatory T cells. J Immunol, 174(8):4803-4811.

[112]MezzadraR, SunC, JaeLT, et al., 2017. Identification of CMTM6 and CMTM4 as PD-L1 protein regulators. Nature, 549(7670):106-110.

[113]MicevicG, ThakralD, McgearyM, et al., 2019. PD-L1 methylation regulates PD-L1 expression and is associated with melanoma survival. Pigment Cell Melanoma Res, 32(3):435-440.

[114]MittendorfEA, PhilipsAV, Meric-BernstamF, et al., 2014. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res, 2(4):361-370.

[115]NagarajuK, RabenN, VillalbaML, et al., 1999. Costimulatory markers in muscle of patients with idiopathic inflammatory myopathies and in cultured muscle cells. Clin Immunol, 92(2):161-169.

[116]NguyenLT, OhashiPS, 2015. Clinical blockade of PD1 and LAG3-potential mechanisms of action. Nat Rev Immunol, 15(1):45-56.

[117]NiL, DongC, 2017. New checkpoints in cancer immunotherapy. Immunol Rev, 276(1):52-65.

[118]NiXY, SuiHX, LiuY, et al., 2012. TGF-‍‍βof lung cancer microenvironment upregulates B7H1 and GITRL expression in dendritic cells and is associated with regulatory T cell generation. Oncol Rep,28(2):615-621.

[119]NoguchiT, WardJP, GubinMM, et al., 2017. Temporally distinct PD-L1 expression by tumor and host cells contributes to immune escape. Cancer Immunol Res, 5(2):‍106-117.

[120]NorrisS, ColemanA, Kuri-CervantesL, et al., 2012. PD-1 expression on natural killer cells and CD8+ T cells during chronic HIV-1 infection. Viral Immunol, 25(4):‍329-332.

[121]OtaK, AzumaK, KawaharaA, et al., 2015. Induction of PD-L1 expression by the EML4-ALK oncoprotein and downstream signaling pathways in non-small cell lung cancer. Clin Cancer Res, 21(17):4014-4021.

[122]OuDW, WangXJ, MetzgerDL, et al., 2006. Suppression of human T-cell responses to β-cells by activation of B7-H4 pathway. Cell Transplant, 15(5):399-410.

[123]OuJN, WiedemanAE, StevensAM, 2012. TNF-‍αand TGF-‍βcounter-regulate PD-L1 expression on monocytes in systemic lupus erythematosus. Sci Rep, 2:295.

[124]Oyewole-SaidD, KonduriV, Vazquez-PerezJ, et al., 2020. Beyond T-cells: functional characterization of CTLA-4 expression in immune and non-immune cell types. Front Immunol, 11:608024.

[125]PaivaP, LockhartMG, GirlingJE, et al., 2016. Identification of genes differentially expressed in menstrual breakdown and repair. Mol Hum Reprod, 22(12):898-912.

[126]PanY, FeiQL, XiongP, et al., 2019. Synergistic inhibition of pancreatic cancer with anti-PD-L1 and c-Myc inhibitor JQ1. Oncoimmunology, 8(5):e1581529.

[127]PandeyP, KhanF, QariHA, et al., 2022. Revolutionization in cancer therapeutics via targeting major immune checkpoints PD-1, PD-L1 and CTLA-4. Pharmaceuticals, 15(3):335.

[128]PardollDM, 2012. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, 12(4):252-264.

[129]PegueroJA, BajajP, CarcerenyE, et al., 2019. A multicenter, phase II study of soluble LAG-3 (Eftilagimod alpha) in combination with pembrolizumab (TACTI-002) in patients with advanced non-small cell lung cancer (NSCLC) or head and neck squamous cell carcinoma (HNSCC). J Clin Oncol, 37(S15):TPS2667.

[130]PengSL, WangR, ZhangXJ, et al., 2019. EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression. Mol Cancer, 18:165.

[131]PetroniG, FormentiSC, Chen-KiangS, et al., 2020. Immunomodulation by anticancer cell cycle inhibitors. Nat Rev Immunol, 20(11):669-679.

[132]PodlesnykhSV, AbramovaKE, GordeevaA, et al., 2021. Peptide blocking CTLA-4 and B7-1 interaction. Molecules, 26(2):253.

[133]PodojilJR, MillerSD, 2017. Potential targeting of B7-H4 for the treatment of cancer. Immunol Rev, 276(1):40-51.

[134]QiuXY, YangS, WangS, et al., 2021. M6A demethylase ALKBH5 regulates PD-L1 expression and tumor immunoenvironment in intrahepatic cholangiocarcinoma. Cancer Res, 81(18):4778-4793.

[135]QuFJ, YeJQ, PanXW, et al., 2019. MicroRNA-497-5p down-regulation increases PD-L1 expression in clear cell renal cell carcinoma. J Drug Target, 27(1):67-74.

[136]QuandtD, Jasinski-BergnerS, MüllerU, et al., 2014. Synergistic effects of IL-4 and TNFα on the induction of B7-H1 in renal cell carcinoma cells inhibiting allogeneic T cell proliferation. J Transl Med, 12:151.

[137]RadichevIA, Maneva-RadichevaLV, AmatyaC, et al., 2016. Loss of peripheral protection in pancreatic islets by proteolysis-driven impairment of VTCN1 (B7-H4) presentation is associated with the development of autoimmune diabetes. J Immunol, 194(4):1495-1506.

[138]RobertC, 2020. A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun, 11:3801.

[139]RotteA, 2019. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res, 38:255.

[140]RowshanravanB, HallidayN, SansomDM, 2018. CTLA-4: a moving target in immunotherapy. Blood, 131(1):58-67.

[141]RuanZY, LiangMH, LaiMX, et al., 2020. KYA1797K down-regulates PD-L1 in colon cancer stem cells to block immune evasion by suppressing the β‍-catenin/STT3 signaling pathway. Int Immunopharmacol, 78:106003.

[142]SchneiderH, MartinM, AgarraberesFA, et al., 1999. Cytolytic T lymphocyte-associated antigen-4 and the TCRζ/CD3 complex, but not CD28, interact with clathrin adaptor complexes AP-1 and AP-2. J Immunol, 163(4):1868-1879.

[143]SchreiberRD, OldLJ, SmythMJ, 2011. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science, 331(6024):1565-1570.

[144]ShaoLL, HouWZ, ScharpingNE, et al., 2019. IRF1 inhibits antitumor immunity through the upregulation of PD-L1 in the tumor cell. Cancer Immunol Res, 7(8):1258-1266.

[145]SharonE, StreicherH, GoncalvesP, et al., 2014. Immune checkpoints in cancer clinical trials. Chin J Cancer, 33(9):434-444.

[146]ShenDD, PangJR, BiYP, et al., 2022. LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in gastric cancer. Mol Cancer, 21:75.

[147]ShenJ, LiSY, MedeirosLJ, et al., 2020. PD-L1 expression is associated with ALK positivity and STAT3 activation, but not outcome in patients with systemic anaplastic large cell lymphoma. Mod Pathol, 33(3):324-333.

[148]ShenMJ, XuLJ, YangL, et al., 2017. Radiation alters PD-L1/NKG2D ligand levels in lung cancer cells and leads to immune escape from NK cell cytotoxicity via IL-6-MEK/Erk signaling pathway. Oncotarget, 8(46):80506-80520.

[149]ShiHB, JiM, WuJ, et al., 2014. Serum B7-H4 expression is a significant prognostic indicator for patients with gastric cancer. World J Surg Oncol, 12:188.

[150]ShinDS, ZaretskyJM, Escuin-OrdinasH, et al., 2017. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov, 7(2):188-201.

[151]ShiratoriT, MiyatakeS, OhnoH, et al., 1997. Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP-2. Immunity, 6(5):583-589.

[152]SicaGL, ChoiIH, ZhuGF, et al., 2003. B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity, 18(6):849-861.

[153]SkafiN, Fayyad-KazanM, BadranB, 2020. Immunomodulatory role for microRNAs: regulation of PD-1/PD-L1 and CTLA-4 immune checkpoints expression. Gene, 754:144888.

[154]StarkeA, WüthrichRP, Waeckerle-MenY, 2007. TGF-beta treatment modulates PD-L1 and CD40 expression in proximal renal tubular epithelial cells and enhances CD8+ cytotoxic T-cell responses. Nephron Exp Nephrol, 107:E22-E29.

[155]StutvoetTS, KolA, de VriesEGE, et al., 2019. MAPK pathway activity plays a key role in PD-L1 expression of lung adenocarcinoma cells. J Pathol, 249(1):52-64.

[156]SuhWK, GajewskaBU, OkadaH, et al., 2003. The B7 family member B7-H3 preferentially down-regulates T helper type 1-mediated immune responses. Nat Immunol, 4(9):899-906.

[157]SunC, LanPX, HanQJ, et al., 2018. Oncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T cell exhaustion. Nat Commun, 9:1241.

[158]SunJR, ZhangX, ZhangY, 2019. MiR-214 prevents the progression of diffuse large B-cell lymphoma by targeting PD-L1. Cell Mol Biol Lett, 24:68.

[159]SunMY, RichardsS, PrasadDVR, et al., 2002. Characterization of mouse and human B7-H3 genes. J Immunol, 168(12):6294-6297.

[160]SunW, ZhangQ, WangRK, et al., 2021. Targeting DNA damage repair for immune checkpoint inhibition: mechanisms and potential clinical applications. Front Oncol, 11:648687.

[161]TanSZ, LiDP, ZhuX, 2020. Cancer immunotherapy: pros, cons and beyond. Biomed Pharmacother, 124:109821.

[162]ThibultML, MamessierE, Gertner-DardenneJ, et al., 2013. PD-1 is a novel regulator of human B-cell activation. Int Immunol, 25(2):129-137.

[163]TopalianSL, TaubeJM, AndersRA, et al., 2016. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer, 16(5):275-287.

[164]TopalianSL, TaubeJM, PardollDM, 2020. Neoadjuvant checkpoint blockade for cancer immunotherapy. Science, 367(6477):eaax0182.

[165]van RensburgHJJ, AzadT, LingM, et al., 2018. The Hippo pathway component TAZ promotes immune evasion in human cancer through PD-L1. Cancer Res, 78(6):‍1457-1470.

[166]WangB, RanZJ, LiuMM, et al., 2019. Prognostic significance of potential immune checkpoint member HHLA2 in human tumors: a comprehensive analysis. Front Immunol, 10:1573.

[167]WangCG, FengHR, ChengX, et al., 2020. Potential therapeutic targets of B7 family in colorectal cancer. Front Immunol, 11:681.

[168]WangJ, JiaY, ZhaoS, et al., 2017. BIN1 reverses PD-L1-mediated immune escape by inactivating the c-MYC and EGFR/MAPK signaling pathways in non-small cell lung cancer. Oncogene, 36(45):6235-6243.

[169]WangJ, SanmamedMF, DatarI, et al., 2019. Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell, 176(1-2):334-347.e12.

[170]WangJ, ZhangRG, LinZY, et al., 2020. CDK7 inhibitor THZ1 enhances antiPD-1 therapy efficacy via the p38α/MYC/PD-L1 signaling in non-small cell lung cancer. J Hematol Oncol, 13:99.

[171]WangJH, WuGP, ManickB, et al., 2019. VSIG-3 as a ligand of VISTA inhibits human T-cell function. Immunology, 156(1):74-85.

[172]WangJY, WangWP, 2020. B7-H4, a promising target for immunotherapy. Cell Immunol, 347:104008.

[173]WangMM, YuWP, GaoJ, et al., 2020. MicroRNA-487a-3p functions as a new tumor suppressor in prostate cancer by targeting CCND1. J Cell Physiol, 235(2):1588-1600.

[174]WangX, LiJG, DongK, et al., 2015. Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia. Cell Signal, 27(3):443-452.

[175]WeiSC, DuffyCR, AllisonJP, 2018. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov, 8(9):1069-1086.

[176]WooSR, TurnisME, GoldbergMV, et al., 2012. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res, 72(4):917-927.

[177]WuQ, JiangL, LiSC, et al., 2021. Small molecule inhibitors targeting the PD-1/PD-L1 signaling pathway. Acta Pharmacol Sin, 42(1):1-9.

[178]WuYQ, BordeM, HeissmeyerV, et al., 2006. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell, 126(2):375-387.

[179]WuYQ, ZhangC, LiuXL, et al., 2021. ARIH1 signaling promotes anti-tumor immunity by targeting PD-L1 for proteasomal degradation. Nat Commun, 12:2346.

[180]WuZ, HuangRT, YuanL, 2019. Crosstalk of intracellular post-translational modifications in cancer. Arch Biochem Biophys, 676:108138.

[181]XieGC, LiW, LiRD, et al., 2017. Helicobacter pylori promote B7-H1 expression by suppressing miR-152 and miR-200b in gastric cancer cells. PLoS ONE, 12(1):e0168822.

[182]XieWB, LiangLH, WuKG, et al., 2018. MiR-140 expression regulates cell proliferation and targets PD-L1 in NSCLC. Cell Physiol Biochem, 46(2):654-663.

[183]XiongWJ, GaoY, WeiWY, et al., 2021. Extracellular and nuclear PD-L1 in modulating cancer immunotherapy. Trends Cancer, 7(9):837-846.

[184]XuLJ, ChenXD, ShenMJ, et al., 2018. Inhibition of IL-6-JAK/Stat3 signaling in castration-resistant prostate cancer cells enhances the NK cell-mediated cytotoxicity via alteration of PD-L1/NKG2D ligand levels. Molr Oncol, 12(3):269-286.

[185]XuSH, TaoZ, HaiB, et al., 2016. miR-424(322) reverses chemoresistance via T-cell immune response activation by blocking the PD-L1 immune checkpoint. Nat Commun, 7:11406.

[186]XuSJ, WangXY, YangYB, et al., 2021. LSD1 silencing contributes to enhanced efficacy of anti-CD47/PD-L1 immunotherapy in cervical cancer. Cell Death Dis, 12(4):282.

[187]XuYP, ZhuSX, SongM, et al., 2014. B7-H4 expression and its role in interleukin-2/interferon treatment of clear cell renal cell carcinoma. Oncol Lett, 7(5):1474-1478.

[188]YamaguchiH, HsuJM, YangWH, et al., 2022. Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics. Nat Rev Clin Oncol, 19(5):287-305.

[189]YamamotoR, NishikoriM, TashimaM, et al., 2009. B7-H1 expression is regulated by MEK/ERK signaling pathway in anaplastic large cell lymphoma and Hodgkin lymphoma. Cancer Sci, 100(11):2093-2100.

[190]YangH, Bueso-RamosC, DinardoC, et al., 2014. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia, 28(6):1280-1288.

[191]YangY, HsuJM, SunL, et al., 2019. Palmitoylation stabilizes PD-L1 to promote breast tumor growth. Cell Res, 29(1):83-86.

[192]YaoH, LanJ, LiCS, et al., 2019. Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumours. Nat Biomed Eng, 3(4):306-317.

[193]YaoS, JiangL, MoserEK, et al., 2015. Control of pathogenic effector T-cell activities in situ by PD-L1 expression on respiratory inflammatory dendritic cells during respiratory syncytial virus infection. Mucosal Immunol, 8(4):746-759.

[194]YiM, NiuMK, XuLP, et al., 2021. Regulation of PD-L1 expression in the tumor microenvironment. J Hematol Oncol, 14:10.

[195]YuanJM, DongXD, YapJ, et al., 2020. The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy. J Hematol Oncol, 13:113.

[196]ZerdesI, MatikasA, BerghJ, et al., 2018. Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations. Oncogene, 37(34):4639-4661.

[197]ZhangGB, ChenYJ, ShiQ, et al., 2004. Human recombinant B7-H3 expressed in E. coli enhances T lymphocyte proliferation and IL-10 secretion in vitro. Acta Biochim Biophys Sin, 36(6):430-436.

[198]ZhangJF, BuX, WangHZ, et al., 2018. Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature, 553(7686):91-95.

[199]ZhangWJ, LiuY, YanZY, et al., 2020. IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma. J Immunother Cancer, 8(1):e000285.

[200]ZhangY, XiangC, WangYL, et al., 2017. PD-L1 promoter methylation mediates the resistance response to anti-PD-1 therapy in NSCLC patients with EGFR-TKI resistance. Oncotarget, 8(60):101535-101544.

[201]ZhangYY, ZhangZM, 2020. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol, 17(8):807-821.

[202]ZhuD, XuRD, HuangXP, et al., 2021. Deubiquitinating enzyme OTUB1 promotes cancer cell immunosuppression via preventing ER-associated degradation of immune checkpoint protein PD-L1. Cell Death Differ, 28(6):‍‍1773-1789.

[203]ZhuTY, HuZH, WangZY, et al., 2020. Epigenetically silenced PD-L1 confers drug resistance to anti-PD1 therapy in gastric cardia adenocarcinoma. Int Immunopharmacol, 82:106245.

[204]ZhuYW, YaoS, IliopoulouBP, et al., 2013. B7-H5 costimulates human T cells via CD28H. Nat Commun, 4:2043.

Open peer comments: Debate/Discuss/Question/Opinion

<1>

Please provide your name, email address and a comment





Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2022 Journal of Zhejiang University-SCIENCE