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Additional Effector T-cell Pathways

LAG-3: impairs T-cell function and can mark exhausted T cells

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 The antigen-presenting complex, major histocompatibility complex (MHC), presents antigen for recognition by T cells and is one of the ligands for LAG-3.2,3 LAG-3 can negatively regulate T-cell proliferation and the development of lasting memory T cells.4

Similar to the expression and function of 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.5,6 Exhausted T cells have an impaired ability to fight tumor cells, which may result in tumor growth.6 T cells co-expressing both LAG-3 and PD-1 may show an even greater degree of exhaustion compared with those expressing LAG-3 alone.7

LAG-3 can also trigger the immunosuppressive activity of Tregs.1 In cancer, Tregs expressing LAG-3 gather at tumor sites and show potent suppression of cytotoxic T cells.8

Increased LAG-3 expression has been associated with poorer prognosis in multiple tumor types.9,10

In preclinical studies, when the PD-1 pathway is blocked, LAG-3 may be upregulated to maintain tumor growth.11 Research is ongoing to understand how dual inhibition of LAG-3 and other checkpoint pathways may synergistically increase T-cell antitumor activity compared with inhibition of either pathway alone.

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.12,13 After these cells have been activated by exposure to tumor antigen, CD137 signals stimulate them to reproduce and to generate antitumor activity.12,13 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.14

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.15

Based on preclinical data, activation of CD137 signaling can stimulate both cytotoxic T-cell and NK-cell activity, and generate a lasting memory response.16,17

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.18,19

Cytotoxic T cells can recognize and attack tumor cells.20 Once exposure to tumor antigen activates a T cell, the number of GITR receptors on its surface increases.18,21 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.22

Exposure to tumor antigen also activates GITR on regulatory T cells (Tregs). Tregs act to limit the immune response.23 GITR signaling can block the suppressive abilities of Tregs, further enhancing cytotoxic T-cell function.23

In preclinical studies, activation of GITR signaling can help enhance immunity through the activation of cytotoxic T cells and inhibition of Treg activity.24

ICOS: co-stimulates T-cell activation and proliferation

Inducible T-cell co-stimulator (ICOS) is an activating receptor expressed on the surface of activated cytotoxic T cells, regulatory T cells (Tregs), NK cells, and other types of T cells.25-29 While similar in structure to the receptor cytotoxic T-lymphocyte antigen 4 (CTLA-4), ICOS has a distinct and opposing function.26,30 The ligand for ICOS—ICOSL (B7RP-1)—is expressed on antigen-presenting cells (APCs) such as dendritic cells (DCs) and macrophages.30,31

ICOS/ICOSL signaling leads to the activation, proliferation, and survival of cytotoxic T cells, as well as the survival of memory T cells.32-34 Following T-cell activation, upregulation of ICOS perpetuates T-cell proliferation and function.33,35 It has been suggested that ICOS/ICOSL signaling may enhance activated NK-cell function.29

In preclinical studies, ICOS signaling was necessary for the activation, proliferation, and function of cytotoxic T cells under native conditions as well as during the blockade of CTLA-4.36,37 This stimulation of ICOS during CTLA-4 blockade was shown to enhance T-cell activity.36 In addition, mouse models demonstrate that ICOS expression may enhance the antitumor response of NK cells.29

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).38-40 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.41-43

Amplification: Tregs act to limit the immune response. OX40-OX40L signaling blocks the ability of Tregs to suppress T cells and reduces Treg generation.44 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.45-47

TIGIT: overpowers cytotoxic T-cell function and proliferation

T-cell immunoreceptor with immunoglobulin and ITIM domains (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.48,49 TIGIT has 2 ligands: CD155 (PVR) and CD112 (Nectin2).48,49 On cytotoxic T cells and NK cells, interaction of TIGIT with either of its ligands suppresses immune activation.48,49 When TIGIT is expressed on Tregs, however, this interaction enhances their ability to suppress the immune response.50

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 CD112.51,52 The inhibitory signal provided by TIGIT overpowers the ability of DNAM1 to stimulate T-cell activation.52

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.53-55

Based on preclinical studies, inhibition of TIGIT signaling increases the proliferation and function of cytotoxic T cells.54,56

TIM-3: exhausts both innate and adaptive effector cells

T-cell immunoglobulin and mucin-3 (TIM-3) is an immune checkpoint receptor involved in the suppression of both innate and adaptive immune cells.57 It is expressed on a wide variety of immune cells, including cytotoxic T cells, regulatory T cells (Tregs), natural killer (NK) cells, and antigen-presenting cells (APCs) such as dendritic cells (DCs).57,58 TIM-3 can suppress effector cells through the interaction with a broad array of ligands: carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1), galectin-9, phosphatidylserine (PS), and high mobility group box 1 (HMGB1).57,59

TIM-3 has multiple suppressive effects on effector T cells.60 Increased T-cell expression of TIM-3 as well as its co-expression with CEACAM1 correlate with T-cell exhaustion.61,62 TIM-3 can also indirectly suppress effector T-cell activity by acting on myeloid-derived suppressor cells (MDSCs), Tregs, and DCs.63-65

  • Binding of TIM-3 on cytotoxic T cells to galectin-9 on immunosuppressive MDSCs can enhance MDSC expansion and suppressor activity.63
  • Expression of TIM-3 on Tregs can reduce T-cell function and proliferation.65
  • The interaction of PS or HMGB1 with TIM-3 on tumor-infiltrating DCs may impair DC ability to activate T-cells and promote inflammation.60,64,66

Increasing expression of TIM-3 on NK cells has also been associated with NK-cell exhaustion.57 In addition, the interaction of TIM-3 on NK cells with galectin-9 or PS can promote their dysfunction.67,68

The expression of TIM-3 is upregulated on NK cells, T cells, and Tregs in various cancers.67,69

Preclinical data suggest that the blockade of TIM-3 can rescue NK-cell activity, promote tumor antigen processing, and reinvigorate exhausted T cells, restoring their proliferation and function.60,61,67,70 TIM-3 is often co-expressed with other immune checkpoint receptors, and preclinical studies indicate that co-blockade of TIM-3 with another immune checkpoint receptor may further reinvigorate exhausted T cells.61,71,72

Oncolytic viruses: attack tumor cells to stimulate T-cell activity

Oncolytic viruses are naturally or genetically engineered viruses that preferentially target and replicate within tumor cells, leading to tumor cell destruction.73-75 Tumor cells often have altered molecular mechanisms favoring viral replication, which may make them uniquely susceptible to viral infection and propagation.75 Similar to immune signaling pathways, viral infection can influence the antitumor immune response.76

To initiate infection, oncolytic viruses recognize and attach to receptors that are highly expressed on tumor cells.74 Once internalized, they replicate and produce viral proteins.74,77 This process ultimately causes host tumor cell lysis, or death, releasing tumor antigens and new viruses into the tumor microenvironment.73,77

Oncolytic viruses can be either “unarmed” or “armed.” Both types of virus can activate an antitumor immune response, in part by promoting tumor inflammation:

  • Unarmed oncolytic viruses lyse host cells, which can lead to the release of tumor antigens that prime and activate cytotoxic T cells to infiltrate and kill the tumor74,77
  • Research is ongoing to determine how armed oncolytic viruses are engineered to initiate tumor-cell expression of immunomodulatory proteins, in addition to lysing host cells. These proteins can further activate the antitumor immune response77-80

Preclinical models demonstrate that unarmed oncolytic viruses can cause the release of tumor antigens, promoting the activation of cytotoxic T cells.81 In addition, immunomodulatory proteins expressed by armed viruses may stimulate tumor inflammation and further enhance cytotoxic T-cell activation as shown in preclinical studies.82-84

Research to further understand these pathways is ongoing.


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