Coinhibitory Receptor Expression and Immune Checkpoint Blockade: Maintaining a Balance in CD8+ T Cell Responses to Chronic Viral Infections and Cancer

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.

Keywords: T cell exhaustion; cancer; checkpoint blockade; chronic infections; immune checkpoints; immunotherapy.

Figure 1

T cell exhaustion: a hierarchical loss of T cell function. Naive T cells differentiate and proliferate into effector cells in response to antigenic challenge. Sustained antigen exposure and T cell receptor (TCR) signaling in response to viral growth or tumor development results in progressive loss of function and concomitant upregulation of multiple coinhibitory receptors by responding cells. Responding T cells either undergo activation-induced cell death (clonal deletion) or exhaustion resulting in compromised memory T cell generation. CTLA-4, cytotoxic T-lymphocyte-associated protein 4; IFN-γ, interferon-gamma; IL-2, interleukin-2; LAG-3, lymphocyte-associated gene 3; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; TIGIT, T cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains; TIM-3, T cell immunoglobulin and mucin domain containing-3, TNF-α, tumor necrosis factor alpha; VISTA, V-domain Ig-containing suppressor of T cell activation.

Figure 2

The phenotype and function of exhausted T cells may be influenced by anatomical location. (A) Diagram depicting T cells in the periphery and lung tumor microenvironment. (B) Progressive exhaustion of T cells occurs with proximity to disease site. Table showing levels of cytokine expression, cytotoxicity, and number of coinhibitory receptors expressed by peripheral, tumor infiltrating and tissue resident T cells.

Figure 3

The onset and sustenance of T cell exhaustion is dependent on persistent antigenic stimulation. Diagram showing the T cell exhaustion gradient, which depends on sustained antigen exposure. The fate of chronically stimulated T cells is either partial or terminal exhaustion, which is associated with a stable chromatin landscape and altered metabolism. Partial-exhausted CD8⁺ T cells can be restored by checkpoint blockade, which leads to differentiation of the proliferative burst.

Figure 4

T cell exhaustion and restoration. This model depicting progressive exhaustion of CD8⁺ T cells during viral infection directly correlates with coexpression of immune checkpoints. Checkpoint blockade implemented by administration of monoclonal antibodies such as α-programmed cell death 1 (α-PD-1) and α-cytotoxic T lymphocyte antigen-4 (α-CTLA-4) restores the function of exhausted T cells.

Figure 5

Coinhibitory receptors may play specific roles in regulating exhausted T cell responses. Severity of exhaustion has been shown to directly correlate with coexpression of multiple coinhibitory receptors on T cells. The diagram shows suggested roles of programmed cell death 1 (PD-1), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte activation gene 3 (LAG-3), cytotoxic T lymphocyte antigen-4 (CTLA-4), and T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) in contributing to T cell exhaustion, such as defective metabolism and cytotoxicity. The roles of other inhibitory receptors such as VISTA and 2B4 are yet to be identified. Coexpressed inhibitory receptors have been shown to synergize and increase the severity of T cell exhaustion. VISTA, V-domain immunoglobulin (Ig)-containing suppressor of T cell activation.