Discovery of New Immune Checkpoints: Family Grows Up

  • Xuan KongEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1248)


The first generation of immune checkpoint inhibitors (ICIs) including anti-CTLA-4 and anti-PD-1/anti-PD-L1 has achieved profound and great success. Till 2019 Q1, there are nine ICIs landing the oncology market: Ipilimumab (anti-CTLA-4, Bristol-Myers Squibb), Nivolumab (anti-PD-1, Bristol-Myers Squibb), Pembrolizumab (anti-PD-1, Merck), Atezolizumab (anti-PD-L1, Roche/Genentech), Durvalumab (anti-PD-L1, Astra Zeneca), Tremelimumab (anti-CTLA-4, Astra Zeneca), Cemiplimab (anti-PD-1, Sanofi/Regeneron), Toripalimab (anti-PD-1, Junshi), and Sintilimab (anti-PD-1, Innovent), which have covered the majority of hematologic and solid malignancies’ indication. Beyond the considerable benefits for the patients, frustrated boundary still exists: limited response rate in monotherapy in late-stage population, poor effectiveness in neoplasms with immune desert and immune excluded types, and immune-related toxicities, some are life-threatened and with higher incidence in I-O combination regiment. Moreover, clinicians observed some cases switching to progression after achieving partial or complete response, indicating treatment failure or drug resistance. So people begin looking for the next generation of immune checkpoint members.


Immune checkpoint inhibitors Receptor identification Ligand screening Cell-based assay T cell inhibition 


  1. Anderson AC, Xiao S, Kuchroo VK (2007) TIM protein structures reveal a unique face for ligand binding. Immunity 26:273–275CrossRefPubMedPubMedCentralGoogle Scholar
  2. Andrews LP, Marciscano AE, Drake CG et al (2017) LAG3 (CD223) as a cancer immunotherapy target. Immunol Rev 276:80–96CrossRefPubMedPubMedCentralGoogle Scholar
  3. Ascierto PA, Melero I, Bhatia S et al (2017) Initial efficacy of anti-lymphocyte activation gene-3 (anti–LAG-3; BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti–PD-1/ PD-L1 therapy. J Clin Oncol 35:9520CrossRefGoogle Scholar
  4. Aspeslagh S, Postel-Vinay S, Rusakiewi S et al (2016) Rationale for anti-OX40 cancer immunotherapy. Eur J Cancer 52:50–66CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bansal-Pakala P, Halteman BS, Cheng MH et al (2004) Costimulation of CD8 T cell responses by OX40. J Immunol 172(8):4821–4825CrossRefPubMedPubMedCentralGoogle Scholar
  6. Beek AA, Zhou GY, Doukas M et al (2019) GITR ligation enhances functionality of tumor-infiltrating T cells in hepatocellular carcinoma. Int J Cancer 145:1119–1124CrossRefGoogle Scholar
  7. Blake SJ, Dougall WC, Miles JJ et al (2016) Molecular pathways: targeting CD96 and TIGIT for cancer immunotherapy. Clin Cancer Res 22:5183–5188CrossRefPubMedPubMedCentralGoogle Scholar
  8. Brignone C, Escudier B, Grygar C et al (2009) 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 15:6225–6231CrossRefPubMedPubMedCentralGoogle Scholar
  9. Chauvin J-M, Pagliano O, Fourcade J et al (2015) TIGIT and PD-1 impair tumor antigen specific CD8 + T cells in melanoma patients. J Clin Invest 125:2046–2058CrossRefPubMedPubMedCentralGoogle Scholar
  10. Cheng L, Ruan ZH (2015) Tim-3 and Tim-4 as the potential targets for antitumor therapy. Hum Vaccines Immunother 11:2458–2462CrossRefGoogle Scholar
  11. Chester C, Ambulkar S, Kohrt HE (2016) 4‑1BB agonism: adding the accelerator to cancer immunotherapy. Cancer Immunol Immunother 65:1243–1248CrossRefPubMedPubMedCentralGoogle Scholar
  12. Chester C, Sanmamed MF, Wang J et al (2018) Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. Blood 131(1):49–57CrossRefGoogle Scholar
  13. Cheuk AT, Mufti GJ, Guinn B (2004) Role of 4-1BB:4-1BB ligand in cancer immunotherapy. Cancer Gene Ther 11:215–226CrossRefGoogle Scholar
  14. Chiba S, Baghdadi M, Akiba H et al (2012) Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat Immunol 13:832–842CrossRefPubMedPubMedCentralGoogle Scholar
  15. Clouthier DL, Watts TH (2014) Cell-specific and context-dependent effects of GITR in cancer, autoimmunity, and infection. Cytokine Growth Factor Rev 25:91–106CrossRefGoogle Scholar
  16. Croft M (2009) The role of TNF superfamily members in T-cell function and diseases. Nat Rev 9:271–285Google Scholar
  17. Curti RD, Kovacsovics-Bankowski M, Morris N et al (2013) OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res 73(24):7189–7198Google Scholar
  18. Das M, Zhu C, Kuchroo VK (2017) Tim-3 and its role in regulating anti-tumor immunity. Immunol Rev 276:97–111CrossRefPubMedPubMedCentralGoogle Scholar
  19. Duhoux FP, Jager A, Dirix L et al (2017) Combination of paclitaxel and LAG3-Ig (IMP321), a novel MHC class II agonist, as a first-line chemo-immunotherapy in patients with metastatic breast carcinoma (MBC): interim results from the run-in phase of a placebo controlled randomized phase II. J Clin Oncol 35:1062CrossRefGoogle Scholar
  20. Freeman GJ, Casasnovas JM, Umetsu DT et al (2010) TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol Rev 235:172–189CrossRefPubMedPubMedCentralGoogle Scholar
  21. Goldberg MV, Drake CG (2011) LAG-3 in cancer immunotherapy. Curr Top Microbiol Immunol 344:269–278PubMedPubMedCentralGoogle Scholar
  22. Gur C, Ibrahim Y, Isaacson B et al (2015) Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity 42:344–355CrossRefPubMedPubMedCentralGoogle Scholar
  23. Gurney AL, Marsters SA, Huang RM et al (1999) Identification of a new member of the tumor necrosis factor family and its receptor, a human ortholog of mouse GITR. Curr Biol CB 9:215–218CrossRefGoogle Scholar
  24. Hamid O, Thompson JA, Diab A et al (2016) First in human (FIH) study of an OX40 agonist monoclonal antibody (mAb) PF-04518600 (PF-8600) in adult patients (pts) with select advanced solid tumors: preliminary safety and pharmacokinetic (PK)/pharmacodynamic results. J Clin Oncol 34:3079–3079CrossRefGoogle Scholar
  25. Han G, Chen G, Shen B et al (2013) Tim-3: an activation marker and activation limiter of innate immune cells. Front Immunol 4:449CrossRefPubMedPubMedCentralGoogle Scholar
  26. Huang YH, Zhu C, Kondo Y et al (2015) CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature 517:386–390CrossRefGoogle Scholar
  27. Huard B, Prigent P, Tournier M et al (1995) CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur J Immunol 25:2718–2721CrossRefGoogle Scholar
  28. Infante JR, Hansen AR, Pishvaian MJ et al (2016) A phase Ib dose escalation study of the OX40 agonist MOXR0916 and the PD-L1 inhibitor atezolizumab in patients with advanced solid tumors. J Clin Oncol 34:101–101CrossRefGoogle Scholar
  29. Joller N, Hafler JP, Brynedal B et al (2011) Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol 186:1338–1342CrossRefPubMedPubMedCentralGoogle Scholar
  30. Joller N, Lozano E, Burkett PR et al (2014) Treg cells expressing the co-inhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 40:569–581CrossRefPubMedPubMedCentralGoogle Scholar
  31. Knee DA, Hewes B, Brogdon JL (2016) Rationale for anti-GITR cancer immunotherapy. Eur J Cancer 67:1–10CrossRefPubMedPubMedCentralGoogle Scholar
  32. Kurtulus S, Sakuishi K, Ngiow S-F et al (2015) TIGIT predominantly regulates the immune response via regulatory T cells. J Clin Invest 125:4053–4062CrossRefPubMedPubMedCentralGoogle Scholar
  33. Lane P (2000) Role of OX40 signals in coordinating CD4 T cell selection, migration, and cytokine differentiation in T helper (Th) 1 and Th2 cells. J Exp Med 191(2):201–206CrossRefPubMedPubMedCentralGoogle Scholar
  34. Lee JJ, Powderly JD, Patel MR et al (2017) Phase 1 trial of CA-170, a novel oral small molecule dual inhibitor of immune checkpoints PD-1 and VISTA, in patients (pts) with advanced solid tumor or lymphomas. J Clin Oncol 35(15_suppl):TPS3099–TPS3099Google Scholar
  35. Linch SN, Redmond WL (2014) Combined OX40 ligation plus CTLA-4 blockade. OncoImmunology 3:e28245CrossRefPubMedPubMedCentralGoogle Scholar
  36. Linch SN, McNamara MJ, Redmond WL (2015) OX40 agonists and combination immunotherapy: putting the pedal to the metal. Front Oncol 5:34Google Scholar
  37. Lines JL, Pantazi E, Mak J et al (2014a) VISTA is an immune checkpoint molecule for human T cells. Cancer Res 74(7):1924–1932CrossRefPubMedPubMedCentralGoogle Scholar
  38. Lines JL, Sempere LF, Broughton T et al (2014b) VISTA is a novel broad-spectrum negative checkpoint regulator for cancer immunotherapy. Cancer Immunol Res 2(6):510–517CrossRefPubMedPubMedCentralGoogle Scholar
  39. Liu J, Qian X, Chen Z et al (2012) Crystal structure of cell adhesion molecule nectin-2/CD112 and its binding to immune receptor DNAM-1/CD226. J. Immunol 188:5511–5520CrossRefPubMedPubMedCentralGoogle Scholar
  40. Liu J, Yuan Y, Chen W et al (2015) Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses. PNAS 112:6682–6687CrossRefGoogle Scholar
  41. Long L, Zhang X, Chen F et al (2018) The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy. Genes Cancer 9(5–6):176–189PubMedPubMedCentralGoogle Scholar
  42. Lozano E, Dominguez-Villar M, Kuchroo V et al (2012) The TIGIT/CD226 axis regulates human T cell function. J Immunol 188:3869–3875CrossRefPubMedPubMedCentralGoogle Scholar
  43. McIntire JJ, Umetsu SE, Akbari O et al (2001) Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat Immunol 2:1109–1116CrossRefGoogle Scholar
  44. Mercier IL, Chen W, Lines JL et al (2014) VISTA regulates the development of protective antitumor immunity. Cancer Res 74(7):1933–1944CrossRefGoogle Scholar
  45. Ngiow SF, von Scheidt B, Akiba H et al (2011) Anti-TIM3 antibody promotes T cell IFN-γ Mediated antitumor immunity and suppresses established tumors. Cancer Res 71:3540–3551CrossRefGoogle Scholar
  46. Nguyen LT, Ohashi PS (2015) Clinical blockade of PD1 and LAG3—potential mechanisms of action. Nat Rev Immunol 15:45–56CrossRefGoogle Scholar
  47. Nowak EC, Lines JL, Varn FS et al (2017) Immunoregulatory functions of VISTA. Immunol Rev 276(1):66–79CrossRefPubMedPubMedCentralGoogle Scholar
  48. Pauken KE, Wherry EJ (2014) TIGIT and CD226: tipping the balance between costimulatory and co-inhibitory molecules to augment the cancer immunotherapy toolkit. Cancer Cell 26:785–787CrossRefPubMedPubMedCentralGoogle Scholar
  49. Rosenzweig M et al (2010) Development of TRX518, an agylcosyl humanized monoclonal antibody (Mab) agonist of huGITR. J Clin Oncol 28:e13028–e13028CrossRefGoogle Scholar
  50. Sakuishi K, Ngiow SF, Sullivan JM et al (2013) TIM3(+)FOXP3(+) regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer. OncoImmunology 2:e23849CrossRefPubMedPubMedCentralGoogle Scholar
  51. Segal NH, Logan TF, Hodi FS et al (2016) Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res 23(8):1929–1936CrossRefGoogle Scholar
  52. Sharma P, Allison JP (2015) Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161:205–214CrossRefPubMedPubMedCentralGoogle Scholar
  53. Shimizu J, Yamazaki S, Takahashi T et al (2002) Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 3:135–142CrossRefPubMedPubMedCentralGoogle Scholar
  54. Siu LL, Steeghs N, Meniawy T et al (2017) Preliminary results of a phase I/IIa study of BMS-986156 (glucocorticoid-induced tumor necrosis factor receptor–related gene [GITR] agonist), alone and in combination with nivolumab in pts with advanced solid tumors. J Clin Oncol 35:104–104CrossRefGoogle Scholar
  55. Solomon BL, Garrido-Laguna I (2018) TIGIT: a novel immunotherapy target moving from bench to bedside. Cancer Immunol Immunother 67:1659–1667CrossRefGoogle Scholar
  56. Stamm H, Wellbrock J, Fiedler W (2018) Interaction of PVR/PVRL2 with TIGIT/DNAM-1 as a novel immune checkpoint axis and therapeutic target in cancer. Mamm Genome 29:694–702CrossRefGoogle Scholar
  57. Stanietsky N, Simic H, Arapovic J et al (2009) The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. PNAS 106:17858–17863CrossRefGoogle Scholar
  58. Sugamura K, Ishii N, Weinberg AD (2004) Therapeutic targeting of the effector T-cell costimulatory molecule OX40. Nat Rev Immunol 4(6):420–431CrossRefGoogle Scholar
  59. Sukumar S, Wilson DC, Yu Y et al (2017) Characterization of MK-4166, a clinical agonistic antibody that targets human GITR and inhibits the generation and suppressive effects of T regulatory cells. Cancer Res 77(16):4378–4388CrossRefGoogle Scholar
  60. Takeda I, Ine S, Killeen N et al (2004) Distinct roles for the OX40-OX40 ligand interaction in regulatory and non-regulatory T cells. J Immunol 172(6):3580–3589CrossRefGoogle Scholar
  61. Tiguea NJ, Bambera L, Andrewsa J et al (2017) MEDI1873, a potent, stabilized hexametric agonist of human GITR with regulatory T-cell targeting potential. OncoImmunology 6(3):e1280645CrossRefGoogle Scholar
  62. Tolcher AW, Sznol M, Hu-Lieskovan S et al (2017) Phase Ib study of utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in combination with pembrolizumab (MK-3475) in patients with advanced solid tumors. Clin Cancer Res 23(18):5349–5357CrossRefGoogle Scholar
  63. Turner JG, Rakhmilevich AL, Burdelya L et al (2001) Anti-CD40 antibody induces antitumor and anti-metastatic effects: the role of NK cells. J Immunol 166:89–94CrossRefGoogle Scholar
  64. Vidard L, Dureui C, Baudhuin J et al (2019) CD137 (4-1BB) engagement fine-tunes synergistic IL-15– and IL-21–driven NK cell proliferation. J Immunol 203:676–685CrossRefGoogle Scholar
  65. Wang L, Rubinstein R, Lines JL et al (2011) VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J Exp Med 208(3):577–592CrossRefPubMedPubMedCentralGoogle Scholar
  66. Willoughby J, Griffiths J, Tews I et al (2017) OX40: structure and function - what questions remain? Mol Immunol 83:13–22CrossRefGoogle Scholar
  67. Woo SR, Turnis ME, Goldberg MV et al (2012) Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res 72:917–927CrossRefGoogle Scholar
  68. Workman CJ, Dugger KJ, Vignali DA (2002) Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3. J Immunol 169:5392–5395CrossRefGoogle Scholar
  69. Xu F, Liu J, Liu D et al (2014) LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Res 74:3418–3428CrossRefGoogle Scholar
  70. Xu W, Hiếu TM, Malarkannan S et al (2018) The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Cell Mol Immunol 15:438–446CrossRefPubMedPubMedCentralGoogle Scholar
  71. Yu X, Harden K, Gonzalez LC et al (2009) The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol 10(1):48–57CrossRefPubMedPubMedCentralGoogle Scholar
  72. Zaini J, Andarini S, Tahara M et al (2007) OX40 ligand expressed by DCs co-stimulates NKT and CD4 + Th cell antitumor immunity in mice. J Clin Invest 117(11):3330–3338CrossRefPubMedPubMedCentralGoogle Scholar
  73. Zhan Y, Gerondakis S, Coghill E et al (2008) Glucocorticoid-induced TNF receptor expression by T cells is reciprocally regulated by NF-kappaB and NFAT. J Immunol 181:5405–5413CrossRefPubMedPubMedCentralGoogle Scholar
  74. Zhu C, Anderson AC, Schubart A et al (2015) The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 6:1245–1252CrossRefGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  1. 1.Bristol Myers Squibb Global Clinical ResearchShanghaiChina

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