Immune Checkpoint Proteins
The immune system is made up of a network of cells, tissues, and organs that work together to protect the body from harmful things like germs, viruses, and diseases like cancer. To function properly, an immune system must detect a wide variety of agents, known as pathogens, from viruses to parasitic worms, and distinguish them from the organism's own healthy tissue. After first finding a foreign substance, the immune system takes action to destroy foreign substances and abnormal cells, including cancer cells.
Fig1. Immune System
There are two main parts of the immune system:
Both an overactive and an underactive immune system can be harmful. Disorders of the immune system can result in autoimmune diseases, inflammatory diseases, and cancer. Immunodeficiency occurs when the immune system is less active than normal, resulting in recurring and life-threatening infections. In humans, immunodeficiency can either be the result of a genetic disease of the use of immunosuppressive medication. In contrast, autoimmunity results from a hyperactive immune system attacking normal tissues.
Cancer and Immune Response
Cancerous cells are actually quite common in the body. Normally, our immune system is able to destroy cancer cells in our bodies. However, sometimes cancer cells can adapt and mutate, effectively hiding from our immune system and allowing cancerous cells to grow and spread. This is how tumors can develop and become a threat to our health.
Immuno-oncology is an innovative area that utilizes the body’s own immune system to fight cancer by modifying it to recognize the tumor as a foreign substance to the body that needs to be attacked. Compared with current treatments for cancer, such as surgery, chemotherapy, and radiation, immuno-oncology allows cancer cells to be targeted, leaving the rest of the cells unharmed. It also has fewer limitations on the stages of cancer that can be targeted.
There are several immuno-oncology treatments that are currently available, such as immune cell therapy (CAR-T), cytokines, monoclonal antibodies, cancer vaccines, and checkpoint inhibitors. Below is a diagram showing the immune checkpoint proteins and their inhibitor drugs.
Immune Checkpoint Proteins
Immune checkpoints are regulators of immune activation. They play a key role in maintaining immune homeostasis and preventing autoimmunity. In cancer, to eradicate tumor cells and induce antitumor immunity, T cells are able to recognize tumor antigens presented to T cell receptors (TCRs) by antigen-presenting cells (APCs). After binding to TCR, a second signal (signal two, also called costimulatory signal) is needed for T cell activation. The costimulatory signal comes from the binding of the CD28 molecule on T cells with its ligand, B-7 molecules (CD80 and CD86) on APCs. After CD28 binds to its ligand, the B7 protein, on the surface of APCs, T cell proliferation is activated to enhance immunity. Cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) transmit inhibitory signals when bound to their ligands, B7-1/B7-2, and PD-L1 (B7-H1)/PD-L2 (B7-DC), respectively, on APCs or tumors. Such protein molecules involved in immune regulation are referred to as immune checkpoints.
As mentioned before, tumor cells can exploit the inhibitory mechanism and evade the host antitumor activity by suppressing the proliferation of immune cells, subsequently survive, and continue to proliferate.
Immune checkpoint inhibitors were developed to control immune escape tumors. Checkpoint inhibitors can block inhibitory checkpoints, restoring immune system function. The most widely studied immune checkpoint inhibitors are anti-CTLA-4, anti-PD-1, and anti-PD-L1 monoclonal antibodies which target the T cell regulatory pathways to augment antitumor immune responses.
Cytotoxic T Lymphocyte antigen 4 (CTLA-4) (CD152) and CD28 are homologous receptors expressed by both CD4+ and CD8+ T cells, which mediate opposing functions in T cell activation. Both receptors share a pair of ligands expressed on the surface of antigen-presenting cells (APCs).
The process of T cell activation is tightly regulated by costimulatory signals for full activation, and it is also regulated by co-inhibitory signals. The main costimulatory signals for T cell activation are from the B7-1 or B7-2 molecules on APC, which can bind to CD28 on T cells. After binding to their specific antigen ligand, the resulting TCR signals in conjunction with the costimulatory signals from CD28/B7 interaction lead to full activation of T cells and production of cytokines. In contrast to CD28, CTLA-4 delivers an inhibitory signal and it has a much higher affinity for B7 than CD28. Thus, CTLA-4 competes to bind to B7 and thereby prevents CD28-mediated T cell co-stimulation while inhibiting T cell activation.
A number of different models have been proposed to explain the mechanism in the function of CTLA-4. The simplest of these involves competition between CD28 and CTLA-4 for ligand binding, which has been proposed alongside other cell-intrinsic inhibitory signaling models. CTLA-4 has a higher binding affinity for B-7 ligands than CD28, which binds these B7 proteins with an approximately 20 times greater affinity and can, therefore, outcompete CD28 for binding, leading to attenuation and termination of T cell responses and establishment of tolerance, to minimize the development of autoimmunity.
While CD28 is constitutively expressed on the plasma membrane and co-stimulates T cells, CTLA-4 is predominantly found in intracellular vesicles in FoxP3+ Treg cells or activated conventional T cells. This localization is due to the constitutive endocytosis of CTLA-4 from the plasma membrane and results in approximately 90% of CTLA-4 being intracellular. One molecular mechanism that is consistent with a dominant cell-extrinsic role for CTLA-4 is the physical capture of CD80 and CD86, and their subsequent removal from APCs: a process known as trans-endocytosis.
The concept of using immune checkpoint inhibitors to break T cell dysfunction in tumor patients appears to be an intriguing approach to cancer therapy. This was first demonstrated by the success of Ipilimumab, an antiCTLA-4 mAb, resulting in the approval of Ipilimumab by the FDA for advanced melanoma.
Initially, PD-1 was demonstrated to be a receptor for cell death; however, the PD-1 pathway was later found to play a regulatory role in inhibiting T cell activation and restraining T cell function. In contrast to CTLA-4, PD-1 predominantly regulates effector T cell activity within tissues and tumors as opposed to regulating T cell activation in lymphoid organs. While CTLA-4 mainly affects naïve T cells, PD-1 is primarily expressed on mature T cells in peripheral tissues and the tumor microenvironment. It is also expressed on other non-T cell subsets including B cells, professional APCs, and natural killer (NK) cells.
PD-L1 and PD-L2 (also referred to as B7-H1 and B7-DC, respectively) are both type I transmembrane proteins. Though PD-L1 is expressed infrequently in normal human tissues outside of the placenta and macrophage-like cells, its expression is upregulated by IFN-γ and other cytokines that are released by activated T cells. In contrast to the positive costimulatory signal delivered by CD28 receptors, PD-1 delivers a negative signal when bound to its ligands, PD-L1, and PD-L2. PD-1 suppresses T cell activation through the recruitment of phosphatase SHP-2 and the subsequent inactivation of Zap 70, which plays a critical role in T-cell receptor signaling.
Cells from many different human tumors can evade host immune surveillance by expressing PD-L1 on their surface. Expression of this immune-checkpoint ligand by tumor cells is thought to be induced by an antitumor immune response. Tumor-infiltrating lymphocytes (TILs) recognize tumor antigens presented by tumor cells, tumor stromal cells, and APCs, and subsequently release IFN-γ to induce PD-L1 expression in these cells, resulting in an adaptive immune resistance microenvironment.
Given the expression of PD-1 on TILs and the upregulation of PD-1 ligands on tumor cells, an anti-tumor host immune response has the foundation. Antibody blockade of PD-1 and its ligands leading to enhanced antitumor immunity in mouse models shows that targeting PD-1 and other immune checkpoints is able to reverse this dysfunctional state and reinvigorate T cell activity in chronic viral infections and cancer.
Other Immune Checkpoint Proteins
Table1. Immune Checkpoint Proteins
|Immune Checkpoint Protein||Synonym||Cellular Expression||Ligand||Function|
|PD-1 (immune-suppressive checkpoint)||CD279||Activated T cells in peripheral tissue, B cells, professional APCs, NK cells||PD-L1 (CD274, B7-H1) and PD-L2(CD273,B7-DC)||PD-1 guards against autoimmunity through a dual mechanism of promoting apoptosis (programmed cell death) in antigen-specific T-cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells).|
|LAG-3 (immune-suppressive checkpoint)||CD223||Activated T cells, NK cells||MHC class II||Involves the unique intracellular KIEELE domain|
|TIM-3 (immune-suppressive checkpoint)||HAVcr2||Activated T cells and tissues such as liver, small intestine, thymus, spleen, lung muscle, brain tissue||Mainly galectin-9, as well as phosphatidylserine and HMGB1||TIM-3 is an immune checkpoint and together with other inhibitory receptors including PD-1 and LAG-3 mediate the CD8+ T-cell exhaustion. HAVCR2 has also been shown as a CD4+ Th1-specific cell surface protein that regulates macrophage activation.|
|CTLA-4 (immune- suppressive checkpoint)||CD152||Mostly naive CD4+ and CD8+ T cells, Tregs||CD80 (B7-1) or CD86 (B7-2)||CTLA-4 is expressed by activated T cells and transmits an inhibitory signal to T cells. CTLA-4 is homologous to the T-cell co-stimulatory protein, CD28, and both molecules bind to CD80 and CD86, on antigen-presenting cells. CTLA-4 binds CD80 and CD86 with greater affinity and avidity than CD28 thus enabling it to outcompete CD28 for its ligands. CTLA4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal. CTLA4 is also found in regulatory T cells and contributes to its inhibitory function. T cell activation through the T cell receptor and CD28 leads to increased expression of CTLA-4.|
|KIRs (immune-suppressive checkpoint)||CD158||Mainly NK cells but also APCs and tumor-associated CTLS||MHC class I molecules (HLAs)||Inhibitory KIRs induce NK cell tolerance through licensing, in which KIR recognizes self MHC class I molecules thus preventing NK cell activation against self-tissue and auto-antigens|
|GITR (immune-activating checkpoint)||CD357||Tregs, activated CD4+ and CD8+ T cells||GITRL||GITR is a surface receptor molecule that has been shown to be involved in inhibiting the suppressive activity of T-regulatory cells and extending the survival of T-effector cells.|
|4-1BB(immune-activating checkpoint)||CD137||Activated CD4+ and CD8+ T cells, Tregs, activated NK cells, DCs, neutrophils||4-1BB-L||This receptor contributes to the clonal expansion, survival, and development of T cells. It can also induce proliferation in peripheral monocytes, enhance T cell apoptosis induced by TCR/CD3 triggered activation, and regulate CD28 co-stimulation to promote Th1 cell responses. TRAF adaptor proteins have been shown to bind to this receptor and transduce the signals leading to activation of NF-kappaB.|
Immune Checkpoint Therapy
Immune checkpoint blockade is game-changing and revolutionary in at least two senses. First, the target for therapy is on immune cells but not tumor cells. Second, the approach is not to attack tumor-specific antigens but to remove an inhibitory pathway.
Recent studies demonstrated that immune checkpoint inhibitors are able to induce durable, long-lasting cancer control. These inhibitors have shown promising efficacy in melanoma, renal cell carcinoma, NSCLC, and bladder UC. As in the case with immunotherapy for other types of cancers, these drugs show a limited response rate, but the efficacy in achieving long-lasting benefits for some patients has changed the paradigm of cancer treatment.
Table2. Some Selected Immunotherapeutic Agents in Clinical Trials
|CTLA-4||Lpilimumab (Yervoy)||IgG1k||Melanoma Non-small/small cell lung cancer||FDA Approved||Bristol-Myers Squibb|
|tremelimumab||IgG2||melanoma||Completed Phase III||Pfizer, now Medimmune|
|PD-1||Nivolumab/BMS-936558/MDX1106||IgG4||melanoma||Phase III||Bristol-Myers Squibb|
|Pidilizumab/CT-011||IgG1||non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, Hodgkin’s lymphoma, multiple myeloma, acute myeloid leukemia||Phase I/II||CureTech|
|BMS-936559/MDX-1105||IgG4||various cancers||Phase I/II||Bristol-Myers Squibb|
|MEDI4736||IgG1k||Select Advanced Malignancies||Phase I||MedImmune/AstraZeneca|
However, we also need to notice that immunotherapy, helping to prompt an “immune response”, can attack healthy cells as well as cancer cells, certain side effects may be experienced, including digestive tract symptoms, loss of appetite, fatigue, and flu-like symptoms.
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