Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Inhibitory receptors and ligands beyond PD-1, PD-L1 and CTLA-4: breakthroughs or backups

Nature Immunology volume 20, pages 1425–1434 (2019)Cite this article

Subjects

Abstract

Although immunotherapeutics targeting the inhibitory receptors (IRs) CTLA-4, PD-1 or PD-L1 have made substantial clinical progress in cancer, a considerable proportion of patients remain unresponsive to treatment. Targeting novel IR–ligand pathways in combination with current immunotherapies may improve clinical outcomes. New clinical immunotherapeutics target T cell–expressed IRs (LAG-3, TIM-3 and TIGIT) as well as inhibitory ligands in the B7 family (B7-H3, B7-H4 and B7-H5), although many of these targets have complex biologies and unclear mechanisms of action. With only modest clinical success in targeting these IRs, current immunotherapeutic design may not be optimal. This Review covers the biology of targeting novel IR–ligand pathways and the current clinical status of their immunotherapeutics, either as monotherapy or in combination with antibody to PD-1 or to its ligand PD-L1. Further understanding of the basic biology of these targets is imperative to the development of effective cancer immunotherapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: LAG-3–ligand interactions and current targeting strategies in the clinic.
Fig. 2: TIM-3–ligand interactions and current targeting strategies in the clinic.
Fig. 3: Complex interactions within the PVR family and current targeting strategies in the clinic.
Fig. 4: Members of the B7 family and targeting strategies in the clinic.

Similar content being viewed by others

References

  1. Francisco, L. M., Sage, P. T. & Sharpe, A. H. The PD-1 pathway in tolerance and autoimmunity. Immunol. Rev. 236, 219–242 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Romo-Tena, J., Gómez-Martín, D. & Alcocer-Varela, J. CTLA-4 and autoimmunity: new insights into the dual regulator of tolerance. Autoimmun. Rev. 12, 1171–1176 (2013).

    CAS  PubMed  Google Scholar 

  3. Ledford, H., Else, H. & Warren, M. Cancer immunologists scoop medicine Nobel prize. Nature 562, 20–21 (2018).

    CAS  PubMed  Google Scholar 

  4. McLane, L. M., Abdel-Hakeem, M. S. & Wherry, E. J. CD8 T cell exhaustion during chronic viral infection and cancer. Annu. Rev. Immunol. 37, 457–495 (2019).

    CAS  PubMed  Google Scholar 

  5. Zarour, H. M. Reversing T-cell dysfunction and exhaustion in cancer. Clin. Cancer Res. 22, 1856–1864 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Schadendorf, D. et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33, 1889–1894 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Della Vittoria Scarpati, G. et al. Ipilimumab in the treatment of metastatic melanoma: management of adverse events. Onco Targets Ther. 7, 203–209 (2014).

    PubMed  PubMed Central  Google Scholar 

  8. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Hamid, O. et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369, 134–144 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562 (2014).

    CAS  PubMed  Google Scholar 

  12. Patel, S. P. & Kurzrock, R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol. Cancer Ther. 14, 847–856 (2015).

    CAS  PubMed  Google Scholar 

  13. Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Andrews, L. P., Marciscano, A. E., Drake, C. G. & Vignali, D. A. LAG3 (CD223) as a cancer immunotherapy target. Immunol. Rev. 276, 80–96 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Woo, S. R. et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 72, 917–927 (2012).

    CAS  PubMed  Google Scholar 

  17. Jing, W. et al. Combined immune checkpoint protein blockade and low dose whole body irradiation as immunotherapy for myeloma. J. Immunother. Cancer 3, 2 (2015).

    PubMed  PubMed Central  Google Scholar 

  18. Foy, S. P. et al. Poxvirus-based active immunotherapy with PD-1 and LAG-3 dual immune checkpoint inhibition overcomes compensatory immune regulation, yielding complete tumor regression in mice. PLoS One 11, e0150084 (2016).

    PubMed  PubMed Central  Google Scholar 

  19. Huang, R. Y. et al. LAG3 and PD1 co-inhibitory molecules collaborate to limit CD8+ T cell signaling and dampen antitumor immunity in a murine ovarian cancer model. Oncotarget 6, 27359–27377 (2015).

    PubMed  PubMed Central  Google Scholar 

  20. Matsuzaki, J. et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc. Natl Acad. Sci. USA 107, 7875–7880 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Huang, C. T. et al. Role of LAG-3 in regulatory T cells. Immunity 21, 503–513 (2004).

    CAS  PubMed  Google Scholar 

  22. Zhang, Q. et al. LAG3 limits regulatory T cell proliferation and function in autoimmune diabetes. Sci. Immunol. 2, eaah4569 (2017).

    PubMed  PubMed Central  Google Scholar 

  23. Gagliani, N. et al. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat. Med. 19, 739–746 (2013).

    CAS  PubMed  Google Scholar 

  24. Workman, C. J. et al. LAG-3 regulates plasmacytoid dendritic cell homeostasis. J. Immunol. 182, 1885–1891 (2009).

    CAS  PubMed  Google Scholar 

  25. Workman, C. J., Rice, D. S., Dugger, K. J., Kurschner, C. & Vignali, D. A. Phenotypic analysis of the murine CD4-related glycoprotein, CD223 (LAG-3). Eur. J. Immunol. 32, 2255–2263 (2002).

    CAS  PubMed  Google Scholar 

  26. 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. 35, 2081–2088 (2005).

    CAS  PubMed  Google Scholar 

  27. Huard, B. et al. Characterization of the major histocompatibility complex class II binding site on LAG-3 protein. Proc. Natl Acad. Sci. USA 94, 5744–5749 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Donia, M. et al. Aberrant expression of MHC class II in melanoma attracts inflammatory tumor-specific CD4+ T-cells, which dampen CD8+ T-cell antitumor reactivity. Cancer Res. 75, 3747–3759 (2015).

    CAS  PubMed  Google Scholar 

  29. Hemon, P. et al. MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis. J. Immunol. 186, 5173–5183 (2011).

    CAS  PubMed  Google Scholar 

  30. Workman, C. J., Dugger, K. J. & Vignali, D. A. Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3. J. Immunol. 169, 5392–5395 (2002).

    CAS  PubMed  Google Scholar 

  31. Xu, F. et al. LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Res. 74, 3418–3428 (2014).

    CAS  PubMed  Google Scholar 

  32. Kouo, 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. 3, 412–423 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang, J. et al. Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell 176, 334–347.e312 (2019).

    CAS  PubMed  Google Scholar 

  34. Ascierto, P. A. et al. Efficacy of BMS-986016, a monoclonal antibody that targets lymphocyte activation gene-3 (LAG-3), in combination with nivolumab in pts with melanoma who progressed during prior anti-PD-1/PD-L1 therapy (mel prior IO) in all-comer and biomarker-enriched populations. Ann. Oncol. 28, 403–440 (2017).

    Google Scholar 

  35. Hong, D. S. et al. Phase I/II study of LAG525 +/− spartalizumab (PDR001) in patients (pts) with advanced malignancies. J. Clin. Oncol. 36, 3012 (2018).

    Google Scholar 

  36. Kraman, M. et al. Dual blockade of PD-L1 and LAG-3 with FS118, a unique bispecific antibody, induces T-cell activation with the potential to drive potent anti-tumour immune responses. J. Immunother. Cancer 5, P348 (2017).

    Google Scholar 

  37. Liu, L. et al. MGD011, a CD19 × CD3 dual-affinity retargeting bi-specific molecule incorporating extended circulating half-life for the treatment of B-cell malignancies. Clin. Cancer Res. 23, 1506–1518 (2017).

    CAS  PubMed  Google Scholar 

  38. Rader, C. DARTs take aim at BiTEs. Blood 117, 4403–4404 (2011).

    CAS  PubMed  Google Scholar 

  39. Das, M., Zhu, C. & Kuchroo, V. K. Tim-3 and its role in regulating anti-tumor immunity. Immunol. Rev. 276, 97–111 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Sakuishi, K. et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207, 2187–2194 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Jin, H. T. et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc. Natl Acad. Sci. USA 107, 14733–14738 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Gao, X. et al. TIM-3 expression characterizes regulatory T cells in tumor tissues and is associated with lung cancer progression. PLoS One 7, e30676 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Fourcade, J. 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. 207, 2175–2186 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Huang, Y. H. et al. CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature 517, 386–390 (2015).

    CAS  PubMed  Google Scholar 

  45. Zhang, Y. et al. Co-expression of TIM-3 and CEACAM1 promotes T cell exhaustion in colorectal cancer patients. Int. Immunopharmacol. 43, 210–218 (2017).

    PubMed  Google Scholar 

  46. Yu, M. et al. Tim-3 is upregulated in human colorectal carcinoma and associated with tumor progression. Mol. Med. Rep. 15, 689–695 (2017).

    CAS  PubMed  Google Scholar 

  47. Zhu, C. et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat. Immunol. 6, 1245–1252 (2005).

    CAS  PubMed  Google Scholar 

  48. DeKruyff, R. H. et al. T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells. J. Immunol. 184, 1918–1930 (2010).

    CAS  PubMed  Google Scholar 

  49. Chiba, S. 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. 13, 832–842 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Dardalhon, V. et al. Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b+Ly-6G+ myeloid cells. J. Immunol. 185, 1383–1392 (2010).

    CAS  PubMed  Google Scholar 

  51. Jie, H. B. et al. Increased PD-1+ and TIM-3+ TILs during cetuximab therapy inversely correlate with response in head and neck cancer patients. Cancer Immunol. Res. 5, 408–416 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Koyama, S. et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat. Commun. 7, 10501 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Ngiow, S. F. et al. Anti-TIM3 antibody promotes T cell IFN-γ-mediated antitumor immunity and suppresses established tumors. Cancer Res. 71, 3540–3551 (2011).

    CAS  PubMed  Google Scholar 

  54. Harding, J. J. et al. A phase Ia/Ib study of an anti-TIM-3 antibody (LY3321367) monotherapy or in combination with an anti-PD-L1 antibody (LY3300054): interim safety, efficacy, and pharmacokinetic findings in advanced cancers. J. Clin. Oncol. 37, 12 (2019).

    Google Scholar 

  55. Sabatos-Peyton, C. A. et al. Blockade of Tim-3 binding to phosphatidylserine and CEACAM1 is a shared feature of anti-Tim-3 antibodies that have functional efficacy. OncoImmunology 7, e1385690 (2018).

    PubMed  Google Scholar 

  56. Sabatos, C. A. et al. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat. Immunol. 4, 1102–1110 (2003).

    CAS  PubMed  Google Scholar 

  57. Isshiki, T. et al. Cutting edge: anti-TIM-3 treatment exacerbates pulmonary inflammation and fibrosis in mice. J. Immunol. 199, 3733–3737 (2017).

    CAS  PubMed  Google Scholar 

  58. Yu, X. et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat. Immunol. 10, 48–57 (2009).

    CAS  PubMed  Google Scholar 

  59. Stanietsky, N. et al. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc. Natl Acad. Sci. USA 106, 17858–17863 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Boles, K. S. et al. A novel molecular interaction for the adhesion of follicular CD4 T cells to follicular DC. Eur. J. Immunol. 39, 695–703 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Dougall, W. C., Kurtulus, S., Smyth, M. J. & Anderson, A. C. TIGIT and CD96: new checkpoint receptor targets for cancer immunotherapy. Immunol. Rev. 276, 112–120 (2017).

    CAS  PubMed  Google Scholar 

  62. Pende, D. et al. Expression of the DNAM-1 ligands, Nectin-2 (CD112) and poliovirus receptor (CD155), on dendritic cells: relevance for natural killer-dendritic cell interaction. Blood 107, 2030–2036 (2006).

    CAS  PubMed  Google Scholar 

  63. Nishiwada, S. et al. Clinical significance of CD155 expression in human pancreatic cancer. Anticancer Res. 35, 2287–2297 (2015).

    CAS  PubMed  Google Scholar 

  64. Joller, N. et al. Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J. Immunol. 186, 1338–1342 (2011).

    CAS  PubMed  Google Scholar 

  65. Whelan, S. et al. PVRIG and PVRL2 are induced in cancer and inhibit CD8+ T-cell function. Cancer Immunol. Res. 7, 257–268 (2019).

    PubMed  PubMed Central  Google Scholar 

  66. Joller, N. et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 40, 569–581 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Anderson, A. C., Joller, N. & Kuchroo, V. K. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44, 989–1004 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Zhu, Y. et al. Identification of CD112R as a novel checkpoint for human T cells. J. Exp. Med. 213, 167–176 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Chauvin, J. M. et al. TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J. Clin. Invest. 125, 2046–2058 (2015).

    PubMed  PubMed Central  Google Scholar 

  70. Fourcade, J. et al. CD226 opposes TIGIT to disrupt Tregs in melanoma. JCI Insight 3, e121157 (2018).

    PubMed Central  Google Scholar 

  71. Brennan, C. A. & Garrett, W. S. Fusobacterium nucleatum - symbiont, opportunist and oncobacterium. Nat. Rev. Microbiol. 17, 156–166 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Gur, C. et al. Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity 42, 344–355 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Johnston, R. J. et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell 26, 923–937 (2014).

    CAS  PubMed  Google Scholar 

  74. Liang, S. et al. Discovery of COM701, a therapeutic antibody targeting the novel immune checkpoint PVRIG, for the treatment of cancer. J. Clin. Oncol. 35, 3074 (2017).

    Google Scholar 

  75. Murter, B. et al. Mouse PVRIG has CD8+ T cell-specific coinhibitory functions and dampens antitumor immunity. Cancer Immunol. Res. 7, 244–256 (2019).

    PubMed  PubMed Central  Google Scholar 

  76. Lucca, L. E. et al. TIGIT signaling restores suppressor function of Th1 Tregs. JCI Insight 4, e124427 (2019).

    PubMed Central  Google Scholar 

  77. Kurtulus, S. et al. TIGIT predominantly regulates the immune response via regulatory T cells. J. Clin. Invest. 125, 4053–4062 (2015).

    PubMed  PubMed Central  Google Scholar 

  78. Loos, M., Hedderich, D. M., Friess, H. & Kleeff, J. B7-h3 and its role in antitumor immunity. Clin. Dev. Immunol. 2010, 683875 (2010).

    PubMed  PubMed Central  Google Scholar 

  79. Sica, G. L. et al. B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity 18, 849–861 (2003).

    CAS  PubMed  Google Scholar 

  80. Wang, L. et al. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J. Exp. Med. 208, 577–592 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Sun, Y. et al. B7-H3 and B7-H4 expression in non-small-cell lung cancer. Lung Cancer 53, 143–151 (2006).

    PubMed  Google Scholar 

  82. Gao, J. et al. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat. Med. 23, 551–555 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Kakavand, H. et al. Negative immune checkpoint regulation by VISTA: a mechanism of acquired resistance to anti-PD-1 therapy in metastatic melanoma patients. Mod. Pathol. 30, 1666–1676 (2017).

    CAS  PubMed  Google Scholar 

  84. Hashiguchi, M. et al. Triggering receptor expressed on myeloid cell-like transcript 2 (TLT-2) is a counter-receptor for B7-H3 and enhances T cell responses. Proc. Natl Acad. Sci. USA 105, 10495–10500 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Yan, R. et al. Murine b7-h3 is a co-stimulatory molecule for T cell activation. Monoclon. Antib. Immunodiagn. Immunother. 32, 395–398 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Chapoval, A. I. et al. B7-H3: a costimulatory molecule for T cell activation and IFN-γ production. Nat. Immunol. 2, 269–274 (2001).

    CAS  PubMed  Google Scholar 

  87. Veenstra, R. G. et al. B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality. Blood 125, 3335–3346 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Leitner, J. et al. B7-H3 is a potent inhibitor of human T-cell activation: No evidence for B7-H3 and TREML2 interaction. Eur. J. Immunol. 39, 1754–1764 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Mao, L. et al. Selective blockade of B7-H3 enhances antitumour immune activity by reducing immature myeloid cells in head and neck squamous cell carcinoma. J. Cell. Mol. Med. 21, 2199–2210 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Jeon, H. et al. Structure and cancer immunotherapy of the B7 family member B7x. Cell Rep. 9, 1089–1098 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Le Mercier, I. et al. VISTA regulates the development of protective antitumor immunity. Cancer Res. 74, 1933–1944 (2014).

    PubMed  Google Scholar 

  92. Blando, J. et al. Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer. Proc. Natl Acad. Sci. USA 116, 1692–1697 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Loo, D. et al. Development of an Fc-enhanced anti-B7-H3 monoclonal antibody with potent antitumor activity. Clin. Cancer Res. 18, 3834–3845 (2012).

    CAS  PubMed  Google Scholar 

  94. Aggarwal, C. et al. A phase 1, open-label, dose-escalation study of enoblituzumab in combination with pembrolizumab in patients with select solid tumors. J. Immunother. Cancer 6, 115 (2018).

    Google Scholar 

  95. Burvenich, I. J. G. et al. Molecular imaging of T cell co-regulator factor B7-H3 with 89Zr-DS-5573a. Theranostics 8, 4199–4209 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Kaplan, C. D. et al. FPA150, a novel B7–H4 therapeutic antibody with checkpoint blockade and ADCC activities. Ann. Oncol. 28, mdx361.005 (2017).

    Google Scholar 

  97. Powderly, J. et al. CA-170, a first in class oral small molecule dual inhibitor of immune checkpoints PD-L1 and VISTA, demonstrates tumor growth inhibition in pre-clinical models and promotes T cell activation in Phase 1 study. Ann. Oncol. 28, mdx376.007 (2017).

    Google Scholar 

  98. Trujillo, J. A., Sweis, R. F., Bao, R. & Luke, J. J. T cell-inflamed versus non-T cell-inflamed tumors: a conceptual framework for cancer immunotherapy drug development and combination therapy selection. Cancer Immunol. Res. 6, 990–1000 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Li, N. et al. Metalloproteases regulate T-cell proliferation and effector function via LAG-3. EMBO J. 26, 494–504 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Möller-Hackbarth, K. et al. A disintegrin and metalloprotease (ADAM) 10 and ADAM17 are major sheddases of T cell immunoglobulin and mucin domain 3 (Tim-3). J. Biol. Chem. 288, 34529–34544 (2013).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank C. Workman, A. Somasundaram, D. Zandberg and J. Luke for comments. Supported by the US National Institutes of Health (P01 AI108545, R01 CA203689, and R01 AI144422 to D.A.A.V.) and an NCI Comprehensive Cancer Center Support CORE grant (CA047904 to D.A.A.V.).

Author information

Authors and Affiliations

  1. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Lawrence P. Andrews, Hiroshi Yano & Dario A. A. Vignali

  2. Graduate Program of Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Hiroshi Yano

  3. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    Dario A. A. Vignali

Authors
  1. Lawrence P. Andrews
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroshi Yano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dario A. A. Vignali
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dario A. A. Vignali.

Ethics declarations

Competing interests

D.A.A.V. has submitted patents covering LAG-3 that are licensed or pending and is entitled to a share in net income generated from licensing of these patent rights for commercial development.

Additional information

Peer review statement Zoltan Fehervari was the primary editor on this review article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Andrews, L.P., Yano, H. & Vignali, D.A.A. Inhibitory receptors and ligands beyond PD-1, PD-L1 and CTLA-4: breakthroughs or backups. Nat Immunol 20, 1425–1434 (2019). https://doi.org/10.1038/s41590-019-0512-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41590-019-0512-0

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer