Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ASCO Annual Meeting 2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

2024 ASCO Annual Meeting

Keep up to date with all the top stories and latest evidence with our hub page, including official congress videos and expert takeaways.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2019

Open Access 01-12-2019 | Solid Tumor | Review

Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4

Authors: Shuang Qin, Linping Xu, Ming Yi, Shengnan Yu, Kongming Wu, Suxia Luo

Published in: Molecular Cancer | Issue 1/2019

Login to get access

Abstract

The emergence of immune checkpoint inhibitors (ICIs), mainly including anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies (mAbs), has shaped therapeutic landscape of some type of cancers. Despite some ICIs have manifested compelling clinical effectiveness in certain tumor types, the majority of patients still showed de novo or adaptive resistance. At present, the overall efficiency of immune checkpoint therapy remains unsatisfactory. Exploring additional immune checkpoint molecules is a hot research topic. Recent studies have identified several new immune checkpoint targets, like lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain Ig suppressor of T cell activation (VISTA), and so on. The investigations about these molecules have generated promising results in preclinical studies and/or clinical trials. In this review, we discussed the structure and expression of these newly-characterized immune checkpoints molecules, presented the current progress and understanding of them. Moreover, we summarized the clinical data pertinent to these recent immune checkpoint molecules as well as their application prospects.
Literature
1.
2.
3.
4.
Ballas ZK. The 2018 Nobel prize in physiology or medicine: an exemplar of bench to bedside in immunology. J Allergy Clin Immunol. 2018;142:1752–3.PubMedCrossRef
5.
Wang J, Yuan R, Song W, Sun J, Liu D, Li Z. PD-1, PD-L1 (B7-H1) and tumor-site immune modulation therapy: the historical perspective. J Hematol Oncol. 2017;10:34.PubMedPubMedCentralCrossRef
6.
Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995;182:459–65.PubMedCrossRef
7.
Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. 2004;4:336–47.PubMedCrossRef
8.
Leach D, Krummel M, Allison J. Enhancement of antitumor immunity by CTLA-4 blockade. Science (New York, NY). 1996;271:1734–6.CrossRef
9.
10.
11.
Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007;19:813–24.PubMedCrossRef
12.
Zhu B, Tang L, Chen S, Yin C, Peng S, Li X, et al. Targeting the upstream transcriptional activator of PD-L1 as an alternative strategy in melanoma therapy. Oncogene. 2018;37:4941–54.PubMedCrossRef
13.
Berger KN, Pu JJ. PD-1 pathway and its clinical application: a 20year journey after discovery of the complete human PD-1 gene. Gene. 2018;638:20–5.PubMedCrossRef
14.
15.
16.
Peters S, Kerr KM, Stahel R. PD-1 blockade in advanced NSCLC: a focus on pembrolizumab. Cancer Treat Rev. 2018;62:39–49.PubMedCrossRef
17.
Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. New Engl J Med. 2017;376:1015–26.PubMedCrossRef
18.
Frenel JS, Le Tourneau C, O'Neil B, Ott PA, Piha-Paul SA, Gomez-Roca C, et al. Safety and efficacy of Pembrolizumab in advanced, programmed death ligand 1-positive cervical cancer: results from the phase Ib KEYNOTE-028 trial. J Clin Oncol. 2017;35:4035–41.PubMedCrossRef
19.
Li Z, Song W, Rubinstein M, Liu D. Recent updates in cancer immunotherapy: a comprehensive review and perspective of the 2018 China cancer immunotherapy workshop in Beijing. J Hematol Oncol. 2018;11:142.PubMedPubMedCentralCrossRef
20.
21.
Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature. 2002;415:536–41.PubMedCrossRef
22.
Yu X, Harden K, Gonzalez LC, Francesco M, Chiang E, Irving B, et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol. 2009;10:48–57.PubMedCrossRef
23.
Wang L, Rubinstein R, Lines JL, Wasiuk A, Ahonen C, Guo Y, et al. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J Exp Med. 2011;208:577–92.PubMedPubMedCentralCrossRef
24.
Chapoval AI, Ni J, Lau JS, Wilcox RA, Flies DB, Liu D, et al. B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nat Immunol. 2001;2:269–74.PubMedCrossRef
25.
Yu X, Zheng Y, Mao R, Su Z, Zhang J. BTLA/HVEM signaling: milestones in research and role in chronic hepatitis B virus infection. Front Immunol. 2019;10:617.PubMedPubMedCentralCrossRef
26.
27.
La-Beck NM, Jean GW, Huynh C, Alzghari SK, Lowe DB. Immune checkpoint inhibitors: new insights and current place in cancer therapy. Pharmacotherapy. 2015;35:963–76.PubMedCrossRef
28.
Lizee G, Overwijk WW, Radvanyi L, Gao J, Sharma P, Hwu P. Harnessing the power of the immune system to target cancer. Annu Rev Med. 2013;64:71–90.PubMedCrossRef
29.
Chambers CA, Kuhns MS, Egen JG, Allison JP. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol. 2001;19:565–94.PubMedCrossRef
30.
31.
Sharma P, Wagner K, Wolchok JD, Allison JP. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat Rev Cancer. 2011;11:805–12.PubMedPubMedCentralCrossRef
32.
33.
34.
35.
36.
Marin-Acevedo JA, Dholaria B, Soyano AE, Knutson KL, Chumsri S, Lou Y. Next generation of immune checkpoint therapy in cancer: new developments and challenges. J Hematol Oncol. 2018;11:39.PubMedPubMedCentralCrossRef
37.
Huang RY, Eppolito C, Lele S, Shrikant P, Matsuzaki J, Odunsi K. LAG3 and PD1 co-inhibitory molecules collaborate to limit CD8+ T cell signaling and dampen antitumor immunity in a murine ovarian cancer model. Oncotarget. 2015;6:27359–77.PubMedPubMedCentral
38.
Huang RY, Francois A, McGray AR, Miliotto A, Odunsi K. Compensatory upregulation of PD-1, LAG-3, and CTLA-4 limits the efficacy of single-agent checkpoint blockade in metastatic ovarian cancer. Oncoimmunology. 2017;6:e1249561.PubMedCrossRef
39.
Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun. 2016;7:10501.PubMedPubMedCentralCrossRef
40.
Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 2010;207:2175–86.PubMedPubMedCentralCrossRef
41.
Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, et al. LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med. 1990;171:1393–405.PubMedCrossRef
42.
Huard B, Mastrangeli R, Prigent P, Bruniquel D, Donini S, El-Tayar N, et al. Characterization of the major histocompatibility complex class II binding site on LAG-3 protein. Proc Natl Acad Sci U S A. 1997;94:5744–9.PubMedPubMedCentralCrossRef
43.
44.
Workman CJ, Vignali DA. The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells. Eur J Immunol. 2003;33:970–9.PubMedCrossRef
45.
Li N, Workman CJ, Martin SM, Vignali DA. Biochemical analysis of the regulatory T cell protein lymphocyte activation gene-3 (LAG-3; CD223). J Immunol. 2004;173:6806–12.PubMedCrossRef
46.
47.
Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, et al. Role of LAG-3 in regulatory T cells. Immunity. 2004;21:503–13.PubMedCrossRef
48.
Huard B, Tournier M, Triebel F. LAG-3 does not define a specific mode of natural killing in human. Immunol Lett. 1998;61:109–12.PubMedCrossRef
49.
Kisielow M, Kisielow J, Capoferri-Sollami G, Karjalainen K. Expression of lymphocyte activation gene 3 (LAG-3) on B cells is induced by T cells. Eur J Immunol. 2005;35:2081–8.PubMedCrossRef
50.
Andreae S, Piras F, Burdin N, Triebel F. Maturation and activation of dendritic cells induced by lymphocyte activation gene-3 (CD223). J Immunol. 2002;168:3874–80.PubMedCrossRef
51.
Huard B, Prigent P, Tournier M, Bruniquel D, Triebel F. CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur J Immunol. 1995;25:2718–21.PubMedCrossRef
52.
Macon-Lemaitre L, Triebel F. The negative regulatory function of the lymphocyte-activation gene-3 co-receptor (CD223) on human T cells. Immunology. 2005;115:170–8.PubMedPubMedCentralCrossRef
53.
Workman CJ, Dugger KJ, Vignali DA. Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3. J Immunol. 2002;169:5392–5.PubMedCrossRef
54.
Baixeras E, Huard B, Miossec C, Jitsukawa S, Martin M, Hercend T, et al. Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens. J Exp Med. 1992;176:327–37.PubMedCrossRef
55.
Kouo T, Huang L, Pucsek AB, Cao M, Solt S, Armstrong T, et al. Galectin-3 shapes antitumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of Plasmacytoid dendritic cells. Cancer Immunol Res. 2015;3:412–23.PubMedPubMedCentralCrossRef
56.
Xu F, Liu J, Liu D, Liu B, Wang M, Hu Z, et al. LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Res. 2014;74:3418–28.PubMedCrossRef
57.
Mao X, Ou MT, Karuppagounder SS, Kam TI, Yin X, Xiong Y, et al. Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science (New York, NY). 2016;353:aah3374
58.
Wang J, Sanmamed MF, Datar I, Su TT, Ji L, Sun J, et al. Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell. 2019;176:334–347.e12.PubMedCrossRef
59.
Prigent P, El Mir S, Dreano M, Triebel F. Lymphocyte activation gene-3 induces tumor regression and antitumor immune responses. Eur J Immunol. 1999;29:3867–76.PubMedCrossRef
60.
Fougeray S, Brignone C, Triebel F. A soluble LAG-3 protein as an immunopotentiator for therapeutic vaccines: preclinical evaluation of IMP321. Vaccine. 2006;24:5426–33.PubMedCrossRef
61.
Huard B, Prigent P, Pages F, Bruniquel D, Triebel F. T cell major histocompatibility complex class II molecules down-regulate CD4+ T cell clone responses following LAG-3 binding. Eur J Immunol. 1996;26:1180–6.PubMedCrossRef
62.
Brignone C, Escudier B, Grygar C, Marcu M, Triebel F. A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma. Clin Cancer Res. 2009;15:6225–31.PubMedCrossRef
63.
Brignone C, Gutierrez M, Mefti F, Brain E, Jarcau R, Cvitkovic F, et al. First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity. J Transl Med. 2010;8:71.PubMedPubMedCentralCrossRef
64.
Wang-Gillam A, Plambeck-Suess S, Goedegebuure P, Simon PO, Mitchem JB, Hornick JR, et al. A phase I study of IMP321 and gemcitabine as the front-line therapy in patients with advanced pancreatic adenocarcinoma. Invest New Drugs. 2013;31:707–13.PubMedCrossRef
65.
Dirix L, Triebel F. AIPAC: a phase IIb study of eftilagimod alpha (IMP321 or LAG-3Ig) added to weekly paclitaxel in patients with metastatic breast cancer. Future Oncol. 2019;15:1963–73.PubMedCrossRef
66.
Romano E, Michielin O, Voelter V, Laurent J, Bichat H, Stravodimou A, et al. MART-1 peptide vaccination plus IMP321 (LAG-3Ig fusion protein) in patients receiving autologous PBMCs after lymphodepletion: results of a phase I trial. J Transl Med. 2014;12:97.PubMedPubMedCentralCrossRef
67.
Legat A, Maby-El Hajjami H, Baumgaertner P, Cagnon L, Abed Maillard S, Geldhof C, et al. Vaccination with LAG-3Ig (IMP321) and peptides induces specific CD4 and CD8 T-cell responses in metastatic melanoma patients--report of a phase I/IIa clinical trial. Clin Cancer Res. 2016;22:1330–40.PubMedCrossRef
68.
Yu X, Huang X, Chen X, Liu J, Wu C, Pu Q, et al. Characterization of a novel anti-human lymphocyte activation gene 3 (LAG-3) antibody for cancer immunotherapy. MAbs. 2019;11:1139–48.PubMedCrossRefPubMedCentral
69.
Wierz M, Pierson S, Guyonnet L, Viry E, Lequeux A, Oudin A, et al. Dual PD1/LAG3 immune checkpoint blockade limits tumor development in a murine model of chronic lymphocytic leukemia. Blood. 2018;131:1617–21.PubMedPubMedCentralCrossRef
70.
Kwiatkowska D, Kluska P, Reich A. Beyond PD-1 immunotherapy in malignant melanoma. Dermatol Ther. 2019;9:243–57.CrossRef
71.
Papadopoulos KP, Lakhani NJ, Johnson ML, Park H, Wang D,Yap TA. A study of REGN3767, an anti-LAG-3 antibody, alone and in combination with cemiplimab (REGN2810), an anti-PD1 antibody, in advanced cancers. J Clin Oncol. 2018;36(suppl):TPS3127.CrossRef
72.
Ghosh S, Sharma G, Travers J, Kumar S, Choi J, Jun HT, et al. TSR-033, a novel therapeutic antibody targeting LAG-3, enhances T-cell function and the activity of PD-1 blockade in vitro and in vivo. Mol Cancer Ther. 2019;18:632–41.PubMedCrossRef
73.
Zettl M, Wurm M, Schaaf O, Tirapu I, Mostbock S, Reschke M, et al. Characterization of the LAG-3 targeting antibody BI 754111 in monotherapy and in combination with the anti-PD-1 antibody BI 754091. Cancer Res. 2018;78(suppl):4547.
74.
Grandal MM, Melander MC, Bhatia VK, Gjetting T, Lindsted T, Frohlich C, et al. Preclinical characterization of Sym022, a novel anti-LAG3 antibody. Cancer Res. 2018;78(suppl):5626.
75.
Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72:917–27.PubMedCrossRef
76.
Kraman M, Fosh N, Kmiecik K, Everett K, Zimarino C, Faroudi M, et al. Dual blockade of PD-L1 and LAG-3 with FS118, a unique bispecific antibody, induces CD8+T-cell activation and modulates the tumor microenvironment to promote antitumor immune responses. Cancer Res. 2018;78(suppl):2719.
77.
La Motte-Mohs R, Shah K, Brown JG, Smith D, Gorlatov S, Ciccarone V, et al. Preclinical characterization of MGD013, a PD-1 x LAG-3 bispecific DART (R) molecule. J Immunother Cancer. 2017;5(suppl 2):P337.
78.
He Y, Cao J, Zhao C, Li X, Zhou C, Hirsch FR. TIM-3, a promising target for cancer immunotherapy. OncoTargets Ther. 2018;11:7005–9.CrossRef
79.
Meyers JH, Sabatos CA, Chakravarti S, Kuchroo VK. The TIM gene family regulates autoimmune and allergic diseases. Trends Mol Med. 2005;11:362–9.PubMedCrossRef
80.
van de Weyer PS, Muehlfeit M, Klose C, Bonventre JV, Walz G, Kuehn EW. A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by its ligand galectin-9. Biochem Biophys Res Commun. 2006;351:571–6.PubMedCrossRef
81.
Anderson AC. Tim-3, a negative regulator of anti-tumor immunity. Curr Opin Immunol. 2012;24:213–6.PubMedCrossRef
82.
Jan M, Chao MP, Cha AC, Alizadeh AA, Gentles AJ, Weissman IL, et al. Prospective separation of normal and leukemic stem cells based on differential expression of TIM3, a human acute myeloid leukemia stem cell marker. Proc Natl Acad Sci U S A. 2011;108:5009–14.PubMedPubMedCentralCrossRef
83.
Huang X, Bai X, Cao Y, Wu J, Huang M, Tang D, et al. Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion. J Exp Med. 2010;207:505–20.PubMedPubMedCentralCrossRef
84.
85.
Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6:1245–52.PubMedCrossRef
86.
Kang CW, Dutta A, Chang LY, Mahalingam J, Lin YC, Chiang JM, et al. Apoptosis of tumor infiltrating effector TIM-3+CD8+ T cells in colon cancer. Sci Rep. 2015;5:15659.PubMedPubMedCentralCrossRef
87.
Chiba S, Baghdadi M, Akiba H, Yoshiyama H, Kinoshita I, Dosaka-Akita H, et al. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat Immunol. 2012;13:832–42.PubMedPubMedCentralCrossRef
88.
Huang YH, Zhu C, Kondo Y, Anderson AC, Gandhi A, Russell A, et al. CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature. 2015;517:386–90.PubMedCrossRef
89.
Nakayama M, Akiba H, Takeda K, Kojima Y, Hashiguchi M, Azuma M, et al. Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood. 2009;113:3821–30.PubMedCrossRef
90.
Zhang Y, Cai P, Liang T, Wang L, Hu L. TIM-3 is a potential prognostic marker for patients with solid tumors: a systematic review and meta-analysis. Oncotarget. 2017;8:31705–13.PubMedPubMedCentral
91.
Hahn AW, Gill DM, Pal SK, Agarwal N. The future of immune checkpoint cancer therapy after PD-1 and CTLA-4. Immunotherapy. 2017;9:681–92.PubMedCrossRef
92.
Murtaza A, Laken H, Correia JDS, McNeeley P, Altobell L, Zhang J, et al. Discovery of TSR-022, a novel, potent anti-human TIM-3 therapeutic antibody. Eur J Cancer. 2016;69(Suppl 1):S102.CrossRef
93.
Chen X, Song X, Li K, Zhang T. FcgammaR-binding is an important functional attribute for immune checkpoint antibodies in cancer immunotherapy. Front Immunol. 2019;10:292.PubMedPubMedCentralCrossRef
94.
Lindsted T, Gad M, Grandal MV, Frolich C, Bhatia VK, Gjetting T, et al. Preclinical characterization of Sym023 a human anti-TIM3 antibody with a novel mechanism of action. Cancer Res. 2018;78(Suppl):5629.
95.
Mollica V, Di Nunno V, Gatto L, Santoni M, Cimadamore A, Cheng L, et al. Novel therapeutic approaches and targets currently under evaluation for renal cell carcinoma: waiting for the revolution. Clin Drug Investig. 2019;39:503–19.PubMedCrossRef
96.
Boles KS, Vermi W, Facchetti F, Fuchs A, Wilson TJ, Diacovo TG, et al. A novel molecular interaction for the adhesion of follicular CD4 T cells to follicular DC. Eur J Immunol. 2009;39:695–703.PubMedPubMedCentralCrossRef
97.
Levin SD, Taft DW, Brandt CS, Bucher C, Howard ED, Chadwick EM, et al. Vstm3 is a member of the CD28 family and an important modulator of T-cell function. Eur J Immunol. 2011;41:902–15.PubMedPubMedCentralCrossRef
98.
Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity. 2016;44:989–1004.PubMedPubMedCentralCrossRef
99.
Stanietsky N, Simic H, Arapovic J, Toporik A, Levy O, Novik A, et al. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci U S A. 2009;106:17858–63.PubMedPubMedCentralCrossRef
100.
Dougall WC, Kurtulus S, Smyth MJ, Anderson AC. TIGIT and CD96: new checkpoint receptor targets for cancer immunotherapy. Immunol Rev. 2017;276:112–20.PubMedCrossRef
101.
102.
Lozano E, Dominguez-Villar M, Kuchroo V, Hafler DA. The TIGIT/CD226 axis regulates human T cell function. J Immunol. 2012;188:3869–75.PubMedCrossRef
103.
Stanietsky N, Rovis TL, Glasner A, Seidel E, Tsukerman P, Yamin R, et al. Mouse TIGIT inhibits NK-cell cytotoxicity upon interaction with PVR. Eur J Immunol. 2013;43:2138–50.PubMedPubMedCentralCrossRef
104.
Liu S, Zhang H, Li M, Hu D, Li C, Ge B, et al. Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells. Cell Death Differ. 2013;20:456–64.PubMedCrossRef
105.
Li M, Xia P, Du Y, Liu S, Huang G, Chen J, et al. T-cell immunoglobulin and ITIM domain (TIGIT) receptor/poliovirus receptor (PVR) ligand engagement suppresses interferon-gamma production of natural killer cells via beta-arrestin 2-mediated negative signaling. J Biol Chem. 2014;289:17647–57.PubMedPubMedCentralCrossRef
106.
Kurtulus S, Sakuishi K, Ngiow SF, Joller N, Tan DJ, Teng MW, et al. TIGIT predominantly regulates the immune response via regulatory T cells. J Clin Invest. 2015;125:4053–62.PubMedPubMedCentralCrossRef
107.
Gur C, Ibrahim Y, Isaacson B, Yamin R, Abed J, Gamliel M, et al. Binding of the Fap2 protein of fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity. 2015;42:344–55.PubMedPubMedCentralCrossRef
108.
Joller N, Hafler JP, Brynedal B, Kassam N, Spoerl S, Levin SD, et al. Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol. 2011;186:1338–42.PubMedCrossRef
109.
Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell. 2014;26:923–37.PubMedCrossRef
110.
Zhang Q, Bi J, Zheng X, Chen Y, Wang H, Wu W, et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol. 2018;19:723–32.PubMedCrossRef
111.
Solomon BL, Garrido-Laguna I. TIGIT: a novel immunotherapy target moving from bench to bedside. Cancer Immunol Immunother. 2018;67:1659–67.PubMedCrossRef
112.
113.
Ceeraz S, Nowak EC, Noelle RJ. B7 family checkpoint regulators in immune regulation and disease. Trends Immunol. 2013;34:556–63.PubMedCrossRef
114.
Lines JL, Pantazi E, Mak J, Sempere LF, Wang L, O'Connell S, et al. VISTA is an immune checkpoint molecule for human T cells. Cancer Res. 2014;74:1924–32.PubMedPubMedCentralCrossRef
115.
Flies DB, Wang S, Xu H, Chen L. Cutting edge: a monoclonal antibody specific for the programmed death-1 homolog prevents graft-versus-host disease in mouse models. J Immunol. 2011;187:1537–41.PubMedCrossRef
116.
117.
Wang JH, Wu GP, Manick B, Hernandez V, Renelt M, Erickson C, et al. VSIG-3 as a ligand of VISTA inhibits human T-cell function. Immunology. 2019;156:74–85.PubMedCrossRef
118.
Le Mercier I, Chen W, Lines JL, Day M, Li J, Sergent P, et al. VISTA regulates the development of protective antitumor immunity. Cancer Res. 2014;74:1933–44.PubMedCrossRef
119.
Dempke WCM, Fenchel K, Uciechowski P, Dale SP. Second- and third-generation drugs for immuno-oncology treatment-the more the better? Eur Cancer (Oxford, England : 1990). 2017;74:55–72.
120.
Blando J, Sharma A, Higa MG, Zhao H, Vence L, Yadav SS, et al. Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer. Proc Natl Acad Sci U S A. 2019;116:1692–7.PubMedPubMedCentralCrossRef
121.
Prasad DV, Nguyen T, Li Z, Yang Y, Duong J, Wang Y, et al. Murine B7-H3 is a negative regulator of T cells. J Immunol. 2004;173:2500–6.PubMedCrossRef
122.
Suh WK, Gajewska BU, Okada H, Gronski MA, Bertram EM, Dawicki W, et al. The B7 family member B7-H3 preferentially down-regulates T helper type 1-mediated immune responses. Nat Immunol. 2003;4:899–906.PubMedCrossRef
123.
Janakiram M, Shah UA, Liu W, Zhao A, Schoenberg MP, Zang X. The third group of the B7-CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7-H3. Immunol Rev. 2017;276:26–39.PubMedPubMedCentralCrossRef
124.
Castellanos JR, Purvis IJ, Labak CM, Guda MR, Tsung AJ, Velpula KK, et al. B7-H3 role in the immune landscape of cancer. Am J Clin Exp Immunol. 2017;6:66–75.PubMedPubMedCentral
125.
Benzon B, Zhao SG, Haffner MC, Takhar M, Erho N, Yousefi K, et al. Correlation of B7-H3 with androgen receptor, immune pathways and poor outcome in prostate cancer: an expression-based analysis. Prostate Cancer Prostatic Dis. 2017;20:28–35.PubMedCrossRef
126.
Ahmed M, Cheng M, Zhao Q, Goldgur Y, Cheal SM, Guo HF, et al. Humanized affinity-matured monoclonal antibody 8H9 has potent antitumor activity and binds to FG loop of tumor antigen B7-H3. J Biol Chem. 2015;290:30018–29.PubMedPubMedCentralCrossRef
127.
Kramer K, Kushner BH, Modak S, Pandit-Taskar N, Smith-Jones P, Zanzonico P, et al. Compartmental intrathecal radioimmunotherapy: results for treatment for metastatic CNS neuroblastoma. J Neurooncol. 2010;97:409–18.PubMedCrossRef
128.
Souweidane MM, Kramer K, Pandit-Taskar N, Zhou Z, Haque S, Zanzonico P, et al. Convection-enhanced delivery for diffuse intrinsic pontine glioma: a single-Centre, dose-escalation, phase 1 trial. Lancet Oncol. 2018;19:1040–50.PubMedPubMedCentralCrossRef
129.
Gavrieli M, Watanabe N, Loftin SK, Murphy TL, Murphy KM. Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of B and T lymphocyte attenuator required for association with protein tyrosine phosphatases SHP-1 and SHP-2. Biochem Biophys Res Commun. 2003;312:1236–43.PubMedCrossRef
130.
Han P, Goularte OD, Rufner K, Wilkinson B, Kaye J. An inhibitory Ig superfamily protein expressed by lymphocytes and APCs is also an early marker of thymocyte positive selection. J Immunol. 2004;172:5931–9.PubMedCrossRef
131.
Sedy JR, Gavrieli M, Potter KG, Hurchla MA, Lindsley RC, Hildner K, et al. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol. 2005;6:90–8.PubMedCrossRef
132.
Steinberg MW, Cheung TC, Ware CF. The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation. Immunol Rev. 2011;244:169–87.PubMedPubMedCentralCrossRef
133.
Murphy KM, Nelson CA, Sedy JR. Balancing co-stimulation and inhibition with BTLA and HVEM. Nat Rev Immunol. 2006;6:671–81.PubMedCrossRef
134.
Cai G, Anumanthan A, Brown JA, Greenfield EA, Zhu B, Freeman GJ. CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator. Nat Immunol. 2008;9:176–85.PubMedCrossRef
135.
136.
Wang J, Sun JW, Liu LN, Flies DB, Nie XX, Toki M, et al. Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy. Nat Med. 2019;25:656–66.PubMedCrossRefPubMedCentral
137.
Metadata
Title
Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4
Authors
Shuang Qin
Linping Xu
Ming Yi
Shengnan Yu
Kongming Wu
Suxia Luo
Publication date
01-12-2019
Publisher
BioMed Central
Keyword
Solid Tumor
Published in
Molecular Cancer / Issue 1/2019
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-019-1091-2

Other articles of this Issue 1/2019

Molecular Cancer 1/2019 Go to the issue

Research

N-Myc promotes therapeutic resistance development of neuroendocrine prostate cancer by differentially regulating miR-421/ATM pathway

Letter to the Editor

Low levels of tumour suppressor miR-655 in plasma contribute to lymphatic progression and poor outcomes in oesophageal squamous cell carcinoma

Research

Circular RNA circSLC8A1 acts as a sponge of miR-130b/miR-494 in suppressing bladder cancer progression via regulating PTEN

Letter to the Editor

Exosomal let-7d-3p and miR-30d-5p as diagnostic biomarkers for non-invasive screening of cervical cancer and its precursors

Review

N6-methyladenosine (m6A) RNA modification in gastrointestinal tract cancers: roles, mechanisms, and applications

Research

Epigenetically upregulated oncoprotein PLCE1 drives esophageal carcinoma angiogenesis and proliferation via activating the PI-PLCε-NF-κB signaling pathway and VEGF-C/ Bcl-2 expression

2024 ASCO Annual Meeting Coverage

Highlights of the Day: Breast cancer – metastatic

Breast Cancer Video

In this session, Dr. Wolff provides his key takeaways from the data presented in the metastatic breast cancer oral abstract session at ASCO 2024.

Watch now

Highlights of the Day: Gynecologic cancer

Gynecologic Cancer Video

Highlights of the Day: Breast Cancer – local/regional/adjuvant

Breast Cancer Video

Neoadjuvant dual immunotherapy improves melanoma outcomes

04-06-2024 Melanoma News

» View more highlights on the ASCO 2024 congress hub page

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits