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Recent advancements in the b7/CD28 immune checkpoint families:new biology and clinical therapeutic strategies

Cellular & Molecular Immunology 2023年第7期20卷 694-713页

作者： Marc C.Pulanco Anne T.Madsen Ankit Tanwar Devin T.Corrigan Xingxing Zang Department of Microbiology and Immunology Albert Einstein College of MedicineNew YorkNY10461USA Department of Urology Albert Einstein College of MedicineNew YorkNY10461USA Department of Oncology Albert Einstein College of MedicineNew YorkNY10461USA Department of Medicine Albert Einstein College of MedicineNew YorkNY10461USA

The b7/CD28 families of immune checkpoints play vital roles in negatively or positively regulating immune cells in homeostasis and various *** basic and clinical studies have revealed novel biology of the b7/CD28 families and new therapeutics for cancer *** this review,we discuss the newly discovered KIR3DL3/TMIGD2/HHLA2 pathways,PD-1/PD-L1 and b7-H3 as metabolic regulators,the glycobiology of PD-1/PD-L1,b7x(b7-H4)and b7-H3,and the recently characterized PD-L1/b7-1 *** also cover the tumor-intrinsic and-extrinsic resistance mechanisms to current anti-PD-1/PD-L1 and anti-CTLA-4 immunotherapies in clinical ***,we review new immunotherapies targeting b7-H3,b7x,PD-1/PD-L1,and CTLA-4 in current clinical trials.

关键词： b7 family immune checkpoints metabolic regulators glycobiology therapy resistance

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A dimeric structure of PD-L1: functional units or evolutionary relics?

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Protein & Cell 2010年第2期1卷 153-160页

作者： Yong Chen Peipei Liu Feng Gao Hao Cheng Jianxun Qi George F.Gao CAS Key Laboratory of Pathogenic Microbiology and Immunology Institute of MicrobiologyChinese Academy of Sciences(CASPMI)Beijing 100101China College of Life Sciences Graduate UniversityChinese Academy of SciencesBeijing 100049China Institute of biophysics Chinese Academy of SciencesBeijing 100101China China-Japan Joint Laboratory of Molecular Immunology and Molecular Microbiology Institute of MicrobiologyChinese Academy of SciencesBeijing 100101China

PD-L1 is a member of the b7 protein family,most of whose members so far were identified as dimers in a solution and crystalline state,either complexed or uncomplexed with their ligand(s).The binding of PD-L1 with its receptor PD-1(CD279)delivers an inhibitory signal regulating the T cell *** with the Garboczi group,we successfully solved another structure of human PD-L1(hPD-L1).Our protein crystallized in the space group of C222_(1) with two hPD-L1 molecules per asymmetric *** comparison of reported b7 structures,we have found some intrinsic factors involved in the interaction of these two *** on these results,we tend to believe this uncomplexed hPD-L1 structure demonstrated its potential dimeric state in solution,althougt it could just be an evolutionary relic,too weak to be detected under present technology,or still a functional unit deserved our attentions.

关键词： PD-L1 crystal structure dimer costimulatory molecules b7 family

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Tumor immune checkpoints and their associated inhibitors

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Journal of Zhejiang University-Science b(biomedicine & biotechnology) 2022年第10期23卷 823-843页

作者： Zerui GAO Xingyi LING Chengyu SHI Ying WANG Aifu LIN MOE Laboratory of biosystem Homeostasis and Protection College of Life SciencesZhejiang UniversityHangzhou 310058China Cancer Center Zhejiang UniversityHangzhou 310058China Key Laboratory for Cell and Gene Engineering of Zhejiang Province Hangzhou 310058China Chu Kochen Honors College of Zhejiang University Hangzhou 310058China breast Center of the First Affiliated Hospital School of MedicineZhejiang UniversityHangzhou 310003China International School of Medicine International Institutes of Medicinethe Fourth Affiliated Hospital of Zhejiang University School of MedicineYiwu 322000China ZJU-QILU Joint Research Institute Hangzhou 310058China

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 *** 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 *** blockade(ICb)therapies targeting these checkpoint molecules have demonstrated significant clinical *** 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 *** the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical *** 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 *** 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.

关键词： Immune checkpoint Immune checkpoint inhibitor Programmed cell death-ligand 1(PD-L1) Cytotoxic T-lymphocyteassociated antigen-4(CTLA-4) Lymphocyte activation gene-3(LAG-3) T-cell immunoglobulin and immunoreceptor tyrosinebased inhibitory motif(ITIM)domain(TIGIT) b7 family

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