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  • Review Article
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Clinical blockade of PD1 and LAG3 — potential mechanisms of action

Nature Reviews Immunology volume 15, pages 45–56 (2015)Cite this article

Subjects

Key Points

  • Negative regulatory receptors, such as PD1 and LAG3, are expressed on 'exhausted' T cells. However, not all cells that express these receptors are exhausted. Therapeutic blockade of the PD1 pathway shows durable clinical responses in patients with melanoma and other types of cancer.

  • The presumed mechanism of action of PD1 blockade is prevention of the interaction between PD1 on tumour-infiltrating T cells and PDL1 expressed on tumour cells. However, PDL1 expression by tumour cells is not an absolute biomarker of clinical response.

  • PD1 has many other functions and pathways that could also be affected by PD1–PDL1 blockade: for example, PD1 and PDL1 are expressed by a variety of cell types in response to a variety of stimuli. PD1 blockade may also perturb other receptor–ligand interactions. Furthermore, 'reverse signalling' can occur through PDL1.

  • The clinical activity of blocking LAG3 is not yet known, but this could potentially induce anti-tumour responses.

  • Triggering of LAG3 on T cells by MHC class II ligands downregulates T cell function, but may also have other immunomodulatory roles. In addition, soluble LAG3 exhibits immune adjuvant activity.

Abstract

Dysfunctional T cells can render the immune system unable to eliminate infections and cancer. Therapeutic targeting of the surface receptors that inhibit T cell function has begun to show remarkable success in clinical trials. In this Review, we discuss the potential mechanisms of action of the clinical agents that target two of these receptors, programmed cell death protein 1 (PD1) and lymphocyte activation gene 3 protein (LAG3). We also suggest correlative studies that may define the predominant mechanisms of action and identify predictive biomarkers.

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Figure 1: Receptors that negatively regulate T cell function.
Figure 2: Mechanisms of action of PD1, PDL1 and PDL2.
Figure 3: The network of receptors and ligands potentially affected by PD1 blockade.
Figure 4: Membrane-bound versus soluble LAG3.

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References

  1. Wherry, E. J. T cell exhaustion. Nature Immunol. 12, 492–499 (2011).

    CAS  Google Scholar 

  2. Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007). This study defines the gene expression profile of T cells during chronic versus acute LCMV infection.

    CAS  PubMed  Google Scholar 

  3. Ahmed, R., Salmi, A., Butler, L. D., Chiller, J. M. & Oldstone, M. B. A. Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice: role in suppression of cytotoxic T lymphocyte response and viral persistence. J. Exp. Med. 60, 521–540 (1984).

    Google Scholar 

  4. Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006). This study shows in the LCMV clone 13 infection model that PD1 blockade can reverse T cell exhaustion and clear chronic viral infection.

    CAS  PubMed  Google Scholar 

  5. Petrovas, C. et al. PD1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J. Exp. Med. 203, 2281–2292 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Trautmann, L. et al. Upregulation of PD1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nature Med. 12, 1198–1202 (2006).

    CAS  PubMed  Google Scholar 

  7. Day, C. L. et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350–354 (2006). References 5–7 show the importance of PD1 in the dysfunction of HIV-specific T cells.

    CAS  PubMed  Google Scholar 

  8. Jones, R. B. et al. TIM3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J. Exp. Med. 205, 2763–2779 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Blackburn, S. D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nature Immunol. 10, 29–37 (2009).

    CAS  Google Scholar 

  10. Matsuzaki, J. et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG3 and PD1 in human ovarian cancer. Proc. Natl Acad. Sci. USA 107, 7875–7880 (2010).

    CAS  PubMed  Google Scholar 

  11. Derre, L. et al. BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination. J. Clin. Invest. 120, 157–167 (2010).

    CAS  PubMed  Google Scholar 

  12. Fourcade, J. et al. Upregulation of TIM3 and PD1 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 

  13. Sakuishi, K. et al. Targeting TIM3 and PD1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207, 2187–2194 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Bengsch, B. et al. Coexpression of PD1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation. PLoS Pathog. 6, e1000947 (2010).

    PubMed  PubMed Central  Google Scholar 

  15. Peretz, Y. et al. CD160 and PD1 co-expression on HIV-specific CD8 T cells defines a subset with advanced dysfunction. PLoS Pathog. 8, e1002840 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Fourcade, J. et al. CD8+ T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD1. Cancer Res. 72, 887–896 (2012).

    CAS  PubMed  Google Scholar 

  17. Horne-Debets, J. M. et al. PD1 dependent exhaustion of CD8+ T cells drives chronic malaria. Cell Rep. 5, 1204–1213 (2013).

    CAS  PubMed  Google Scholar 

  18. Ezinne, C. C., Yoshimitsu, M., White, Y. & Arima, N. HTLV-1 specific CD8+ T cell function augmented by blockade of 2B4/CD48 interaction in HTLV-1 infection. PLoS ONE 9, e87631 (2014).

    PubMed  PubMed Central  Google Scholar 

  19. Baitsch, L. et al. Exhaustion of tumor-specific CD8 T cells in metastases from melanoma patients. J. Clin. Invest. 121, 2350–2360 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Baitsch, L. et al. Extended co-expression of inhibitory receptors by human CD8 T-cells depending on differentiation, antigen-specificity and anatomical localization. PLoS ONE 7, e30852 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Krummel, M. F. & Allison, J. P. CD28 and CTLA4 have opposing effects on the response of T cells to stimulation. J. Exp. Med. 182, 459–465 (1995).

    CAS  PubMed  Google Scholar 

  22. Waterhouse, P. et al. Lymphoproliferative disorders with early lethality in mice deficient in CTLA4. Science 270, 985–988 (1995).

    CAS  PubMed  Google Scholar 

  23. Tivol, E. A. et al. Loss of CTLA4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA4. Immunity 3, 541–547 (1995).

    CAS  PubMed  Google Scholar 

  24. Takahashi, T. et al. Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 192, 303–310 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Read, S., Malmstrom, V. & Powrie, F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation. J. Exp. Med. 192, 295–302 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Peggs, K. S., Quezada, S. A., Chambers, C. A., Korman, A. J. & Allison, J. P. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J. Exp. Med. 206, 1717–1725 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Shiratori, T. et al. Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP-2. Immunity 6, 583–589 (1997).

    CAS  PubMed  Google Scholar 

  28. Ishida, Y., Agata, Y., Shibahara, K. & Honjo, T. Induced expression of PD1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 11, 3887–3895 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Dong, H., Zhu, G., Tamada, K. & Chen, L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nature Med. 5, 1365–1369 (1999).

    CAS  PubMed  Google Scholar 

  30. Freeman, G. J. et al. Engagement of the PD1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Latchman, Y. et al. PDL2 is a second ligand for PD1 and inhibits T cell activation. Nature Immunol. 2, 261–268 (2001).

    CAS  Google Scholar 

  32. Tseng, S. Y. et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J. Exp. Med. 193, 839–846 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Keir, M. E., Butte, M. J., Freeman, G. J. & Sharpe, A. H. PD1 and its ligands in tolerance and immunity. Ann. Rev. Immunol. 26, 677–704 (2008).

    CAS  Google Scholar 

  34. Okazaki, T. & Honjo, T. The PD1-PDL pathway in immunological tolerance. Trends Immunol. 27, 195–201 (2006).

    CAS  PubMed  Google Scholar 

  35. Okazaki, T., Chikuma, S., Iwai, Y., Fagarasan, S. & Honjo, T. A rheostat for immune responses: the unique properties of PD1 and their advantages for clinical application. Nature Immunol. 14, 1212–1218 (2013).

    CAS  Google Scholar 

  36. Iwai, Y. et al. Involvement of PDL1 on tumor cells in the escape from host immune system and tumor immunotherapy by PDL1 blockade. Proc. Natl Acad. Sci. USA 99, 12293–12297 (2002).

    CAS  PubMed  Google Scholar 

  37. Dong, H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nature Med. 8, 793–800 (2002).

    CAS  PubMed  Google Scholar 

  38. Sznol, M. & Chen, L. Antagonist antibodies to PD1 and B7-H1 (PDL1) in the treatment of advanced human cancer. Clin. Cancer Res. 19, 1021–1034 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Gardiner, D. et al. A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD1), in patients with chronic hepatitis C virus infection. PLoS ONE 8, e63818 (2013).

    PubMed  PubMed Central  Google Scholar 

  40. Brahmer, J. R. et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167–3175 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Topalian, S. L. et al. Safety, activity, and immune correlates of anti–PD1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 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 

  43. Weber, J. S. et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J. Clin. Oncol. 31, 4311–4318 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Topalian, S. L. et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32, 1020–1030 (2014). This paper is the most recently published follow-up report on data from the nivolumab clinical trials, showing durable clinical responses in patients with metastatic melanoma.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Hamid, O. et al. Safety and tumor responses with lambrolizumab (anti-PD1) in melanoma. N. Engl. J. Med. 369, 134–144 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Robert, C. et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384, 1109–1117 (2014). This paper is the most recent published update from a pembrolizumab clinical trial.

    CAS  PubMed  Google Scholar 

  47. Berger, R. et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD1, in patients with advanced hematologic malignancies. Clin. Cancer Res. 14, 3044–3051 (2008). This is the first-in-human clinical trial of PD1 pathway blockade that was published.

    CAS  PubMed  Google Scholar 

  48. Armand, P. et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J. Clin. Oncol. 31, 4199–4206 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Westin, J. R. et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol. 15, 69–77 (2014).

    CAS  PubMed  Google Scholar 

  50. Brahmer, J. R. et al. Safety and activity of anti–PDL1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Velcheti, V. et al. Programmed death ligand-1 expression in non-small cell lung cancer. Lab. Invest. 94, 107–116 (2014).

    CAS  PubMed  Google Scholar 

  52. Taube, J. M. et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl. Med. 4, 127ra37 (2012).

    PubMed  PubMed Central  Google Scholar 

  53. Lipson, E. J. et al. PDL1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival. Cancer Immunol. Res. 1, 54–63 (2013).

    CAS  PubMed  Google Scholar 

  54. Spranger, S. et al. Upregulation of PD-L1, IDO, and TRegs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci. Transl. Med. 5, 200ra116 (2013).

    PubMed  PubMed Central  Google Scholar 

  55. Brown, J. A. et al. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J. Immunol. 170, 1257–1266 (2003).

    CAS  PubMed  Google Scholar 

  56. Kinter, A. L. et al. The common γ-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J. Immunol. 181, 6738–6746 (2008).

    CAS  PubMed  Google Scholar 

  57. Kryczek, I. et al. Cutting edge: IFNγ enables APC to promote memory TH17 and abate TH1 cell development. J. Immunol. 181, 5842–5846 (2008).

    CAS  PubMed  Google Scholar 

  58. Devaud, C., John, L. B., Westwood, J. A., Darcy, P. K. & Kershaw, M. H. Immune modulation of the tumor microenvironment for enhancing cancer immunotherapy. Oncoimmunology 2, e25961 (2013).

    PubMed  PubMed Central  Google Scholar 

  59. Mueller, S. N. et al. PDL1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice. J. Clin. Invest. 120, 2508–2515 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Curiel, T. J. et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nature Med. 9, 562–567 (2003).

    CAS  PubMed  Google Scholar 

  61. Ding, Z. C. et al. Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses through the PD1–PDL1 axis. Cancer Res. 74, 3441–3453 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Wang, W. et al. PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+ CD25hi regulatory T cells. Int. Immunol. 21, 1065–1077 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Francisco, L. M. et al. PDL1 regulates the development, maintenance, and function of induced regulatory T cells. J. Exp. Med. 206, 3015–3029 (2009). This study describes the importance of PDL1 in the development and the maintenance of pT Reg cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Mazanet, M. M. & Hughes, C. C. B7-H1 is expressed by human endothelial cells and suppresses T cell cytokine synthesis. J. Immunol. 169, 3581–3588 (2002).

    CAS  PubMed  Google Scholar 

  65. Rodig, N. et al. Endothelial expression of PDL1 and PDL2 downregulates CD8+ T cell activation and cytolysis. Eur. J. Immunol. 33, 3117–3126 (2003).

    CAS  PubMed  Google Scholar 

  66. Grabie, N. et al. Endothelial programmed death-1 ligand 1 (PDL1) regulates CD8+ T-cell mediated injury in the heart. Circulation 116, 2062–2071 (2007).

    CAS  PubMed  Google Scholar 

  67. Rozali, E. N., Hato, S. V., Robinson, B. W., Lake, R. A. & Lesterhuis, W. J. Programmed death ligand 2 in cancer-induced immune suppression. Clin. Dev. Immunol. 2012, 656340 (2012).

    PubMed  PubMed Central  Google Scholar 

  68. Xiao, Y. et al. RGMB is a novel binding partner for PDL2 and its engagement with PDL2 promotes respiratory tolerance. J. Exp. Med. 211, 943–959 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Zinselmeyer, B. H. et al. PD1 promotes immune exhaustion by inducing antiviral T cell motility paralysis. J. Exp. Med. 210, 757–774 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Hunder, N. N. et al. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N. Engl. J. Med. 358, 2698–2703 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Tran, E. et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344, 641–645 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Raziorrouh, B. et al. Inhibitory phenotype of HBV-specific CD4+ T-cells is characterized by high PD1 expression but absent coregulation of multiple inhibitory molecules. PLoS ONE 9, e105703 (2014).

    PubMed  PubMed Central  Google Scholar 

  73. Gu-Trantien, C. et al. CD4+ follicular helper T cell infiltration predicts breast cancer survival. J. Clin. Invest. 123, 2873–2892 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Yao, S. et al. PD1 on dendritic cells impedes innate immunity against bacterial infection. Blood 113, 5811–5818 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Said, E. A. et al. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nature Med. 16, 452–459 (2010).

    CAS  PubMed  Google Scholar 

  76. Huang, A. et al. Myeloid-derived suppressor cells regulate immune response in patients with chronic hepatitis B virus infection through PD1-Induced IL-10. J. Immunol. 193, 5461–5469 (2014).

    CAS  PubMed  Google Scholar 

  77. Hirano, F. et al. Blockade of B7-H1 and PD1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 65, 1089–1096 (2005).

    CAS  PubMed  Google Scholar 

  78. Azuma, T. et al. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood 111, 3635–3643 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Kuipers, H. et al. Contribution of the PD1 ligands/PD1 signaling pathway to dendritic cell-mediated CD4+ T cell activation. Eur. J. Immunol. 36, 2472–2482 (2006).

    CAS  PubMed  Google Scholar 

  80. Noman, M. Z. et al. PDL1 is a novel direct target of HIF1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 211, 781–790 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Alvarez, I. B. et al. Role played by the programmed death-1-programmed death ligand pathway during innate immunity against Mycobacterium tuberculosis. J. Infect. Dis. 202, 524–532 (2010).

    CAS  PubMed  Google Scholar 

  82. Norris, S. et al. PD1 expression on natural killer cells and CD8+ T cells during chronic HIV-1 infection. Viral Immunol. 25, 329–332 (2012).

    CAS  PubMed  Google Scholar 

  83. Hardy, B., Galli, M., Rivlin, E., Goren, L. & Novogrodsky, A. Activation of human lymphocytes by a monoclonal antibody to B lymphoblastoid cells; molecular mass and distribution of binding protein. Cancer Immunol. Immunother. 40, 376–382 (1995).

    CAS  PubMed  Google Scholar 

  84. Benson, D. M. Jr et al. The PD1/PDL1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD1 antibody. Blood 116, 2286–2294 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Nishimura, H., Nose, M., Hiai, H., Minato, N. & Honjo, T. Development of lupus-like autoimmune diseases by disruption of the PD1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11, 141–151 (1999). This paper is the first description of the role of PD1 in autoimmunity.

    CAS  PubMed  Google Scholar 

  86. Nishimura, H. et al. Autoimmune dilated cardiomyopathy in PD1 receptor-deficient mice. Science 291, 319–322 (2001).

    CAS  PubMed  Google Scholar 

  87. Haynes, N. M. et al. Role of CXCR5 and CCR7 in follicular TH cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation. J. Immunol. 179, 5099–5108 (2007).

    CAS  PubMed  Google Scholar 

  88. Thibult, M. L. et al. PD1 is a novel regulator of human B-cell activation. Int. Immunol. 25, 129–137 (2013).

    CAS  PubMed  Google Scholar 

  89. Gotot, J. et al. Regulatory T cells use programmed death 1 ligands to directly suppress autoreactive B cells in vivo. Proc. Natl Acad. Sci. USA 109, 10468–10473 (2012).

    CAS  PubMed  Google Scholar 

  90. Titanji, K. et al. Acute depletion of activated memory B cells involves the PD1 pathway in rapidly progressing SIV-infected macaques. J. Clin. Invest. 120, 3878–3890 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Butte, M. J., Keir, M. E., Phamduy, T. B., Sharpe, A. H. & Freeman, G. J. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27, 111–122 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Wang, S. et al. Molecular modeling and functional mapping of B7-H1 and B7-DC uncouple costimulatory function from PD1 interaction. J. Exp. Med. 197, 1083–1091 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Liu, X. et al. B7DC/PDL2 promotes tumor immunity by a PD1-independent mechanism. J. Exp. Med. 197, 1721–1730 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Shin, T. et al. Cooperative B7-1/2 (CD80/CD86) and B7-DC costimulation of CD4+ T cells independent of the PD1 receptor. J. Exp. Med. 198, 31–38 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Taube, J. M. et al. Association of PD1, PD1 ligands, and other features of the tumor immune microenvironment with response to anti-PD1 therapy. Clin. Cancer Res. 20, 5064–5074 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Triebel, F. et al. LAG3, a novel lymphocyte activation gene closely related to CD4. J. Exp. Med. 171, 1393–1405 (1990). This paper describes the identification of LAG3.

    CAS  PubMed  Google Scholar 

  97. Workman, C. J., Rice, D. S., Dugger, K. J., Kurschner, C. & Vignali, D. A. Phenotypic analysis of the murine CD4-related glycoprotein, CD223 (LAG3). Eur. J. Immunol. 32, 2255–2263 (2002).

    CAS  PubMed  Google Scholar 

  98. Sierro, S., Romero, P. & Speiser, D. E. The CD4-like molecule LAG3, biology and therapeutic applications. Expert Opin. Ther. Targets 15, 91–101 (2011).

    CAS  PubMed  Google Scholar 

  99. Huard, B., Tournier, M., Hercend, T., Triebel, F. & Faure, F. Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes. Eur. J. Immunol. 24, 3216–3221 (1994).

    CAS  PubMed  Google Scholar 

  100. Workman, C. J. et al. Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J. Immunol. 172, 5450–5455 (2004).

    CAS  PubMed  Google Scholar 

  101. Richter, K., Agnellini, P. & Oxenius, A. On the role of the inhibitory receptor LAG3 in acute and chronic LCMV infection. Int. Immunol. 22, 13–23 (2010).

    CAS  PubMed  Google Scholar 

  102. Butler, N. S. et al. Therapeutic blockade of PDL1 and LAG3 rapidly clears established blood-stage Plasmodium infection. Nature Immunol. 13, 188–195 (2012).

    CAS  Google Scholar 

  103. Demeure, C. E., Wolfers, J., Martin-Garcia, N., Gaulard, P. & Triebel, F. T. Lymphocytes infiltrating various tumour types express the MHC class II ligand lymphocyte activation gene-3 (LAG3): role of LAG3/MHC class II interactions in cell-cell contacts. Eur. J. Cancer 37, 1709–1718 (2001).

    CAS  PubMed  Google Scholar 

  104. Grosso, J. F. et al. LAG3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J. Clin. Invest. 117, 3383–3392 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Woo, S. R. et al. Immune inhibitory molecules LAG3 and PD1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 72, 917–927 (2012).

    CAS  PubMed  Google Scholar 

  106. Goding, S. R. et al. Restoring immune function of tumor-specific CD4+ T cells during recurrence of melanoma. J. Immunol. 190, 4899–4909 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Huang, C. T. et al. Role of LAG3 in regulatory T cells. Immunity 21, 503–513 (2004).

    CAS  PubMed  Google Scholar 

  108. Sega, E. I. et al. Role of lymphocyte activation gene-3 (LAG3) in conventional and regulatory T cell function in allogeneic transplantation. PLoS ONE 9, e86551 (2014).

    PubMed  PubMed Central  Google Scholar 

  109. Kisielow, M., Kisielow, J., Capoferri-Sollami, G. & Karjalainen, K. Expression of lymphocyte activation gene 3 (LAG3) on B cells is induced by T cells. Eur. J. Immunol. 35, 2081–2088 (2005).

    CAS  PubMed  Google Scholar 

  110. Workman, C. J. & Vignali, D. A. Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223). J. Immunol. 174, 688–695 (2005).

    CAS  PubMed  Google Scholar 

  111. Hemon, P. et al. MHC class II engagement by its ligand LAG3 (CD223) contributes to melanoma resistance to apoptosis. J. Immunol. 186, 5173–5183 (2011).

    CAS  PubMed  Google Scholar 

  112. Brignone, C., Grygar, C., Marcu, M., Schakel, K. & Triebel, F. A soluble form of lymphocyte activation gene-3 (IMP321) induces activation of a large range of human effector cytotoxic cells. J. Immunol. 179, 4202–4211 (2007). This paper describes the soluble LAG3 reagent that went on to be tested for immune adjuvant activity in clinical trials.

    CAS  PubMed  Google Scholar 

  113. Prigent, P., El Mir, S., Dreano, M. & Triebel, F. Lymphocyte activation gene-3 induces tumor regression and antitumor immune responses. Eur. J. Immunol. 29, 3867–3876 (1999).

    CAS  PubMed  Google Scholar 

  114. Casati, C. et al. Soluble human LAG3 molecule amplifies the in vitro generation of type 1 tumor-specific immunity. Cancer Res. 66, 4450–4460 (2006).

    CAS  PubMed  Google Scholar 

  115. Triebel, F., Hacene, K. & Pichon, M. F. A soluble lymphocyte activation gene-3 (sLAG3) protein as a prognostic factor in human breast cancer expressing estrogen or progesterone receptors. Cancer Lett. 235, 147–153 (2006).

    CAS  PubMed  Google Scholar 

  116. Brignone, C., Grygar, C., Marcu, M., Perrin, G. & Triebel, F. IMP321 (sLAG3) safety and T cell response potentiation using an influenza vaccine as a model antigen: a single-blind phase I study. Vaccine 25, 4641–4650 (2007).

    CAS  PubMed  Google Scholar 

  117. 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. 15, 6225–6231 (2009).

    CAS  PubMed  Google Scholar 

  118. Brignone, C. et al. First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG3Ig) enhances immune responses and antitumor activity. J. Transl. Med. 8, 71 (2010).

    PubMed  PubMed Central  Google Scholar 

  119. Romano, E. et al. MART1 peptide vaccination plus IMP321 (LAG3Ig fusion protein) in patients receiving autologous PBMCs after lymphodepletion: results of a Phase I trial. J. Transl. Med. 12, 97 (2014).

    PubMed  PubMed Central  Google Scholar 

  120. Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 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 

  122. Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. http://dx.doi.org/10.1056/NEJMoa1412082 (2014).

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Acknowledgements

The authors thank O. Chan for her contributions to this article.

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Authors and Affiliations

  1. Immune Therapy Program, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, M5G 2M9, Ontario, Canada

    Linh T. Nguyen & Pamela S. Ohashi

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  1. Linh T. Nguyen
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  2. Pamela S. Ohashi
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Correspondence to Linh T. Nguyen or Pamela S. Ohashi.

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Glossary

Exhaustion

A state of impaired T cell function that results from chronic exposure to an antigen.

Inhibitory receptors

Receptors that negatively regulate cellular function. They may contain immunoreceptor tyrosine-based inhibition (ITIM) motifs. The absence of such receptors or their inhibition by antagonistic antibodies leads to improved cell function.

Merkel cell

A cell type in the epithelium that is essential for the fine resolution of sensory stimuli; this cell type is malignantly transformed in Merkel cell carcinoma.

Two-photon intravital microscopy

Laser-scanning microscopy that uses near-infrared laser light for the excitation of conventional fluorophores or fluorescent proteins. Owing to the deep tissue penetration of light, the main advantage is the ability to visualize live and intact specimens.

T follicular helper cells

(TFH cells). CD4+ T helper cells that function in providing help for B cell responses, including the formation of germinal centres and differentiation of B cells into antibody-producing plasma cells.

Germinal centre

Located in peripheral lymphoid tissues (for example, the spleen), these structures are sites of B cell proliferation and selection for clones that produce antigen-specific antibodies of higher affinity.

Recombination-activating gene

(RAG). RAG1 and RAG2 are essential for the rearrangement process that generates diversity in T cell receptor and antibody loci. Mice that are deficient for either of these genes fail to produce B cells or T cells owing to a developmental block in the gene rearrangement that is necessary for antigen receptor expression.

Objective responses

Reductions in tumour burden that satisfy the criteria for a complete or partial response.

Trogocytosis

A process in which a cell can acquire portions of the cell membrane and molecules within the membrane from another cell. The term is generally used for immune cells.

Adjuvant

An agent that improves an immune response, generally acting via stimulating antigen-presenting cells.

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Nguyen, L., Ohashi, P. Clinical blockade of PD1 and LAG3 — potential mechanisms of action. Nat Rev Immunol 15, 45–56 (2015). https://doi.org/10.1038/nri3790

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