Abstract
In cancer and chronic viral infections, T cells are exposed to persistent antigen stimulation. This results in expression of multiple inhibitory receptors also called “immune checkpoints” by T cells. Although these inhibitory receptors under normal conditions maintain self-tolerance and prevent immunopathology, their sustained expression deteriorates T cell function: a phenomenon called exhaustion. Recent advances in cancer immunotherapy involve blockade of cytotoxic T lymphocyte antigen-4 and programmed cell death 1 in order to reverse T cell exhaustion and reinvigorate immunity, which has translated to dramatic clinical remission in many cases of metastatic melanoma and lung cancer. With the paucity of therapeutic vaccines against chronic infections such as HIV, HPV, hepatitis B, and hepatitis C, such adjunct checkpoint blockade strategies are required including the blockade of other inhibitory receptors such as T cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif domains, T cell Ig and mucin-domain containing-3, lymphocyte activation gene 3, and V-domain Ig-containing suppressor of T cell activation. The nature of different chronic viral infections and cancers is likely to influence the level, composition, and pattern of inhibitory receptors expressed by responding T cells. This will have implications for checkpoint antibody blockade strategies employed for treating tumors and chronic viral infections. Here, we review recent advances that provide a clearer insight into the role of coinhibitory receptor expression in T cell exhaustion and reveal novel antibody-blockade therapeutic targets for chronic viral infections and cancer. Understanding the mechanism of T cell exhaustion in response to chronic virus infections and cancer as well as the nature of restored T cell responses will contribute to further improvement of immune checkpoint blockade strategies.
Highlights
The mammalian immune system functions to protect the host from challenge by a milieu of foreign antigens as well as prevention of autoimmunity by limiting recognition of self-antigens
A number of immunecheckpoint blockade studies have demonstrated that targeting a combination of programmed cell death 1 (PD-1) and other coinhibitory receptors such as cytotoxic T lymphocyte antigen-4 (CTLA-4), TIM-3, CD160, TIGIT, and lymphocyte activation gene 3 (LAG-3) have facilitated restoration of CD8+ T cell function depicted by increased proliferation, IFN-γ and IL-2 production, and cytotoxicity [59,60,61,62,63]
In a recent study by Tirosh et al results from single cell RNA sequencing of CD8+ T cells from melanoma tumors identified a core exhaustion signature independent of T cell activation, comprising of genes encoding inhibitory receptors (TIM-3, PD-1, LAG-3, CTLA-4) and NFATC1 [49]
Summary
The mammalian immune system functions to protect the host from challenge by a milieu of foreign antigens as well as prevention of autoimmunity by limiting recognition of self-antigens. A number of immunecheckpoint blockade studies have demonstrated that targeting a combination of PD-1 and other coinhibitory receptors such as CTLA-4, TIM-3, CD160, TIGIT, and LAG-3 have facilitated restoration of CD8+ T cell function depicted by increased proliferation, IFN-γ and IL-2 production, and cytotoxicity [59,60,61,62,63]. It is unclear, whether blockade of PD-1 is a major prerequisite for reversal of exhaustion. PD-1 utilizes a two-pronged approach to influence the nature and extent of exhaustion by promoting survival of antigen-responsive T cells [32] and controlling their localization and function [70]
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