Coinhibitory receptors serve as immune checkpoints against unrestrained T cell activation by limiting the costimulatory signaling and ligation pathways. These receptors also play an important role during active infection and inflammation by maintaining peripheral tolerance and immune system homeostasis.
CTLA-4 + CD86 (B7-2)
Cytotoxic T lymphocyte antigen 4 (CTLA-4) is expressed exclusively on the surface of activated T cells and counteracts the activity of costimulatory receptor CD28 upon antigen recognition. Upregulation of CTLA-4 dampens the downstream signaling of TCR and CD28 by competing with CD28 for its ligands CD80/86 (B7-1/B7-2). Due to its greater affinity for the B7 ligands, it outcompetes CD28, resulting in inhibition of both T cell activation and proliferation. Competition between CD28 and CTLA-4 for binding to B7 ligands ensures the balance of the immune system is preserved and inhibits overactivation of the immune response and enhanced autoimmunity. Additionally, CTLA-4 is constitutively expressed on Treg cells, enhancing Treg cell’s suppression of the T cell anti-tumor immune response.
Tumor cells utilize the CTLA-4 pathway to suppress initiation of the immune response, leading to decreased T cell activation and proliferation into memory T cells, which are key to mounting an effective long-term immune response against tumor antigens. Therefore, blocking the CTLA-4 inhibitory pathway using immunotherapy can help restore the immune anti-tumor response by increasing accumulation, function and survival of T cells and memory T cells, while inhibiting Treg activity. Inhibition of effector T cell differentiation, memory generation and enhancement of effector T cell exhaustion highlights another prime reason CTLA-4 is a target for immunotherapy.
PD-1 + CD274 (PD-L1; B7-1)
PD-1 plays a vital role in maintaining physiologically-appropriate T cell responses and limiting the activity of effector T cells in peripheral organs to prevent immune-mediated tissue damage. PD-1 is expressed in early stages of T cell activation on the surface of CD4+, CD8+ and regulatory T cells, NK cells, B cells and activated monocytes. PD-1 can interact with either of two coinhibitory ligands PD-L1 (CD274; B7-H1) or PD-L2 (CD273). Co-stimulation of PD-1 with PD-L1 leads to increased T cell apoptosis, inhibition of both proliferation and cytokine production in order to prevent autoimmune diseases, and inflammation. PD-L1’s ability to compete with CD28 and CTLA-4 for binding CD80 provides a bi-directional inhibitory immune response. PD-1/PD-L2 binding inhibits T cell proliferation, cytokine production and apoptosis by blocking cell cycle progression.
Several cancers use this pathway to evade immune destruction. Thus, blocking PD-1/B7-H1 has the potential to protect T cells from exhaustion and enhance immunity against cancer. Deficiencies in PD-1 are associated with various autoimmune diseases. Uncontrolled PD-1 expression, as is seen in the cancer environment, results in enhanced T cell exhaustion, thereby decreasing the anti-tumor response of T cells. Over time, the exhausted T cells become disabled and lose their ability to function, reproduce and fight tumor cells. PD-L1 and PD-L2 are expressed in multiple solid tumors, including renal cancer, melanoma and non-small cell lung cancer. Research has shown that enhanced expression of PD-L1 is a potential biomarker for poor survival in patients with advanced tumor stages. Decreased PD-L2 expression has been associated with longer median survival times in certain cancers. Inhibiting PD-1 binding to both PD-L1 and PD-L2 has shown to increase response rates in patients with metastatic cancer. Combination immunotherapy inducing a co-blockade of PD-1 and CTLA-4 could enhance therapeutic efficacy by mitigating their suppression of the immune response and reinvigorating exhausted T cells. Additionally, stimulation of these pathways could also be of interest in downregulation of immune responses during transplant rejection and autoimmune diseases.
LAG3 pathway: MHC + LAG3
Lymphocyte-activation gene 3 (LAG3) is an immune checkpoint receptor involved in downregulation of T cell-mediated immune response and is expressed on activated cytotoxic T cells, Tregs and NK cells. Upon binding to MHC, LAG3 signaling downregulates T cell proliferation and development of memory T cells. T cells that co-express LAG3 and PD-1 are thought to increase T cell exhaustion to a greater degree than either signal alone. Repeated exposure to a tumor antigen increases the expression and activity of LAG3 leading to enhanced T cell exhaustion, which is often seen in a variety of cancers. Elevated LAG3 expression has also been associated with tumor-infiltrating Tregs in various cancer types. Dual blockage of LAG3 with other immune checkpoint receptors, including PD-1, hold promise as strong immunotherapeutic options by mitigating the effects of T cell exhaustion.
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