The blockade of immune checkpoints in cancer immunotherapy

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Wing, K. et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271–275 (2008). A T Reg cell-specific Ctla4 -knockout approach to prove that CTLA4 has a role in T Reg cell function that is independent of its role in modulating the amplitude of effector T cell activation.

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Yuan, J. et al. Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab. Proc. Natl Acad. Sci. USA. 108, 16723–16728 (2011).

Liakou, C. I. et al. CTLA-4 blockade increases IFNγ-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc. Natl Acad. Sci. USA 105, 14987–14992 (2008).

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Freeman, G. J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000). The demonstration that PD1 is the receptor for PDL1.

Keir, M. E. et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J. Exp. Med. 203, 883–895 (2006).

Nishimura, H. et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291, 319–322 (2001).

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Okazaki, T. & Honjo, T. PD-1 and PD-1 ligands: from discovery to clinical application. Int. Immunol. 19, 813–824 (2007).

Keir, M. E., Butte, M. J., Freeman, G. J. & Sharpe, A. H. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26, 677–704 (2008).

Dong, H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nature Med. 8, 793–800 (2002). The crucial demonstration that PDL1 is upregulated on tumour cells and that PDL1 expression on tumour cells mediates immune resistance.

Blank, C. et al. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 64, 1140–1145 (2004).

Taube, J. M. et al. B7-H1 expression co-localizes with inflammatory infiltrates in benign and malignant melanocytic lesions: implications for immunotherapy. Sci. Transl. Med. (In the press, 2012). Introduction of the adaptive immune resistance hypothesis that proposes that the expression of immune-checkpoint ligand by tumours can be induced by an antitumour immune response as an adaptive immune-protective mechanism.

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Lasaro, M. O. et al. Active immunotherapy combined with blockade of a coinhibitory pathway achieves regression of large tumor masses in cancer-prone mice. Mol. Ther. 19, 1727–1736 (2011).

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 PD-1. Cancer Res. 72, 887–896 (2012).

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Li, B. et al. Anti-programmed death-1 synergizes with granulocyte macrophage colony-stimulating factor—secreting tumor cell immunotherapy providing therapeutic benefit to mice with established tumors. Clin. Cancer Res. 15, 1623–1634 (2009).

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