PD-1 and LAG-3 in Cancer Immunotherapy


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Charles Drake
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, USA

Abstract

Programmed Death-1 (PD-1) and its two ligands, PD-L1(B7-H1) and PD-L2(B7-DC), play important roles in infectious immunity, cancer immunity and autoimmunity. Mechanistically, PD-1 engagement can induce T cell apoptosis - but the PD-1 /PD-L1 interaction can also inhibit proliferative responses as well as cytokine release in response to TCR signalling. Direct evidence that PD-1 represents an inhibitory receptor came from analysis of PD-1 knockout mice, which develop strain-specific autoimmunity later in life. Most of the inhibitory roles of PD-1 on T cell responses have been attributed to its interaction with PD-L1. Recent clinical data support a mechanism of ‘adaptive immune resistance', in which interferon-gamma mediates the up-regulation of PD-L1 by tumours; and this molecule in turn serves to protect them from immune attack. In some ways, this mechanism most likely represents a reflection of the normal expression of PD-L1 within peripheral tissues, where expression during acute injury serves to protect tissues from bystander immune attack. Clinically, blocking PD-1 with a specific monoclonal antibody has resulted in objective responses in patients with renal cell carcinoma, melanoma, colorectal cancer and perhaps most interestingly in non-small cell lung cancer (NSCLC). In addition to PD-1, several other cell surface molecules expressed on CD8 T cells serve as immune ‘checkpoints', limiting or abrogating an antigen-specific response. One particularly interesting molecule in this regard is LAG-3 (lymphocyte activation gene-3). Data from our group and others showed that the PD-1 and LAG-3 down-modulate CD8 T cell function by distinct pathways, such that blockade of these checkpoints is synergistic in restoring an anti-tumour immune response. Correspondingly, PD-1 blockade has relatively subtle effects on the kinetics of a primary CD8 T cell response to vaccination, whereas combining PD-1 blockade with blockade of LAG-3 results in more dramatic effects on CD8 T cell trafficking and effector function. Taken together, these data suggest a more personalised approach to cancer immunotherapy, in which several immune checkpoint molecules are blocked simultaneously.

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