Additional Effector T Cell Pathways

LAG-3: implicated in both T-cell exhaustion and suppression

Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor expressed on the surface of both activated cytotoxic T cells and regulatory T cells (Tregs).^1,2 LAG-3 binds to the antigen-MHC complex, which presents antigen for recognition by T cells. LAG-3 can negatively regulate T-cell proliferation and development of lasting memory T cells.³

Similar to PD-1, repeated exposure to tumor antigen causes a continual increase in the presence and activity of LAG-3. This unrelenting signaling leads to T-cell exhaustion—steadily eroding the ability of T cells to kill tumor cells.^4,5 In preclinical studies, inactivation of LAG-3 allowed T cells to regain cytotoxic function.⁶

Within the immune system, Tregs suppress the immune response and are triggered by LAG-3. In cancer, Tregs expressing LAG-3 gather at tumor sites and show potent suppression of cytotoxic T cells.^1,7

CD137: potentiator of innate and adaptive immunity

CD137, or 4-1BB, is an activating receptor. Because it appears on both Natural Killer (NK) cells and T cells, CD137 can trigger both innate and adaptive immunity.^8,9 After these cells have been activated by exposure to tumor antigen, CD137 signals stimulate them to reproduce and to generate antitumor activity.^8,9 In animal models, CD137 also plays a critical role on T cells in the development of immune memory and the creation of a durable immune response.¹⁰

On lymphocytes, the presence of CD137 appears to be a marker for tumor reactivity—the ability to react to tumor antigen and mount an immune response.¹¹

Based on preclinical data, activation of CD137 signaling can stimulate both cytotoxic T-cell and NK-cell activity, and generate a lasting memory response.^12,13

GITR: energizes the T-cell response to antigen

Glucocorticoid-induced TNFR-related protein (GITR) is an activating receptor on the surface of T cells and other immune cells.^14,15

Cytotoxic T cells can recognize and attack tumor cells. Once exposure to tumor antigen activates a T cell, the number of GITR receptors on its surface increases.¹⁴ On the activated T cell, GITR acts as a costimulatory receptor, meaning that it is a receptor whose signaling enhances cell reproduction and the generation of cancer-killing activity.¹⁶

Exposure to tumor antigen also activates GITR on regulatory T cells (Tregs). Tregs act to limit the immune response. GITR signaling can block the suppressive abilities of Tregs, further enhancing cytotoxic T-cell function.¹⁷

In preclinical studies, activation of GITR signaling can help enhance immunity through the activation of cytotoxic T cells and inhibition of Treg activity.¹⁸

OX40: activates and amplifies T-cell stimulation

OX40 is an activating receptor expressed on the surface of activated cytotoxic T cells and regulatory T cells (Tregs).^19-21 OX40 plays a dual role in the immune response, both activating and amplifying T-cell responses.

Activation: Cytotoxic T cells are able to recognize and attack tumor cells. On cytotoxic T cells, OX40 binds to its ligand (OX40L), resulting in stimulatory signals that promote T-cell reproduction, function, and survival.^22-24
Amplification: Tregs act to limit the immune response. OX40-OX40L signaling blocks the ability of Tregs to suppress T cells and reduces Treg generation.²⁵ By inhibiting the immunosuppressive effect of Tregs and limiting their population, OX40 further amplifies the impact of T-cell activation.

The dual effects of OX40 help create a tumor microenvironment that is more favorable to the antitumor immune response. Cytotoxic T cells are increased in number and activity, and the immunosuppressive impact of Tregs is curtailed. These shifts have been demonstrated in preclinical studies of OX40 signaling.^26-28

TIGIT: overpowers cytotoxic T-cell function and proliferation

T cell Ig and ITIM domain (TIGIT) is an immune checkpoint receptor expressed on the surface of cytotoxic, memory, and regulatory T cells (Tregs), as well as Natural Killer (NK) cells.^29,30 TIGIT has 2 ligands: CD155 (PVR) and CD112 (Nectin2).^29,30 On cytotoxic T cells and NK cells, interaction of TIGIT with either of its ligands suppresses immune activation.^29,30 When TIGIT is expressed on Tregs, however, this interaction enhances the ability to suppress the immune response.³¹

In the normal immune system, the suppressive effect of TIGIT is counterbalanced by the immune-activating receptor CD226 (also called DNAM1). Also expressed on cytotoxic T cells and NK cells, DNAM1 competes with TIGIT to bind to CD155 and CD112.^32,33 The inhibitory signal provided by TIGIT overpowers the ability of DNAM1 to stimulate T-cell activation.

Tumor cells exploit the dominance of the inhibitory TIGIT pathway to avoid immune-mediated destruction. In cancer, increased presence of TIGIT and its ligands is associated with impaired DNAM1 signaling and a progressive loss of T-cell function through a process known as T-cell exhaustion.^34-36

Based on preclinical studies, inhibition of TIGIT signaling increases the proliferation and function of cytotoxic T cells.^35,37

Research to further understand these pathways is ongoing.

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References

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