Immune checkpoint

Last updated November 20, 2024

Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulating immune checkpoint targets.^[1]

Inhibitory checkpoint molecules are targets for cancer immunotherapy due to their potential for use in multiple types of cancers. Currently approved checkpoint inhibitors block CTLA4, PD-1 and PD-L1. For the related basic science discoveries, James P. Allison and Tasuku Honjo won the Tang Prize in Biopharmaceutical Science and the Nobel Prize in Physiology or Medicine in 2018.^[2]^[3]

Stimulatory checkpoint molecules

Four stimulatory checkpoint molecules are members of the tumor necrosis factor (TNF) receptor superfamily—CD27, CD40, OX40, GITR and CD137. Another two stimulatory checkpoint molecules belong to the B7-CD28 superfamily—CD28 itself and ICOS.

CD27: This molecule supports antigen-specific expansion of naïve T cells and is vital for the generation of T cell memory.^[4] CD27 is also a memory marker of B cells.^[5] CD27's activity is governed by the transient availability of its ligand, CD70, on lymphocytes and dendritic cells.^[6] CD27 costimulation is known to suppress Th17 effector cell function.^[7] The American biotech company Celldex Therapeutics is working on CDX-1127, an agonistic anti-CD27 monoclonal antibody ^[8] which in animal models has been shown to be effective in the context of T cell receptor stimulation.^[9]
CD28: This molecule is constitutively expressed on almost all human CD4+ T cells and on around half of all CD8 T cells. Binding with its two ligands are CD80 and CD86, expressed on dendritic cells, prompts T cell expansion. CD28 was the target of the TGN1412 'superagonist' which caused severe inflammatory reactions in the first-in-man study in London in March 2006.^[10]
CD40: This molecule, found on a variety of immune system cells including antigen presenting cells has CD40L, otherwise known as CD154 and transiently expressed on the surface of activated CD4+ T cells, as its ligand. CD40 signaling is known to ‘license’ dendritic cells to mature and thereby trigger T-cell activation and differentiation.^[11] A now-defunct Seattle-based biotechnology company called VLST in-licensed an anti-CD40 agonist monoclonal antibody from Pfizer in 2012. The Swiss pharmaceutical company Roche acquired this project when VLST was shut down in 2013.^[12]
CD122: This molecule, which is the Interleukin-2 receptor beta sub-unit, is known to increase proliferation of CD8+ effector T cells.^[13] The American biotechnology company Nektar Therapeutics is working on NKTR-214, a CD122-biased immune-stimulatory cytokine^[14] Phase I results announced in Nov 2016.^[15]
CD137: When this molecule, also called 4-1BB, is bound by CD137 ligand, the result is T-cell proliferation. CD137-mediated signaling is also known to protect T cells, and in particular, CD8+ T cells from activation-induced cell death.^[16] The German biotech company Pieris Pharmaceuticals has developed an engineered lipocalin that is bi-specific for CD137 and HER2.^[17]
OX40: This molecule, also called CD134, has OX40L, or CD252, as its ligand. Like CD27, OX40 promotes the expansion of effector and memory T cells, however it is also noted for its ability to suppress the differentiation and activity of T-regulatory cells, and also for its regulation of cytokine production.^[18] OX40's value as a drug target primarily lies in the fact that, being transiently expressed after T-cell receptor engagement, it is only upregulated on the most recently antigen-activated T cells within inflammatory lesions.^[19] Anti-OX40 monoclonal antibodies have been shown to have clinical utility in advanced cancer.^[20] The pharma company AstraZeneca has three drugs in development targeting OX40: MEDI0562 is a humanised OX40 agonist; MEDI6469, murine OX4 agonist; and MEDI6383, an OX40 agonist^[21]
GITR: short for Glucocorticoid-Induced TNFR family Related gene, prompts T cell expansion, including Treg expansion.^[22] The ligand for GITR is mainly expressed on antigen presenting cells.^[23] Antibodies to GITR have been shown to promote an anti-tumor response through loss of Treg lineage stability.^[24] The biotech company TG Therapeutics is working on anti-GITR antibodies^[25]
ICOS: This molecule, short for Inducible T-cell costimulator, and also called CD278, is expressed on activated T cells. Its ligand is ICOSL, expressed mainly on B cells and dendritic cells. The molecule seems to be important in T cell effector function.^[26] The American biotechnology company Jounce Therapeutics is developing an ICOS agonist.

Inhibitory checkpoint molecules

A2AR & A2BR: The Adenosine A2A receptor is regarded as an important checkpoint in cancer therapy because adenosine in the immune microenvironment, leading to the activation of the A2a receptor, is negative immune feedback loop and the tumor microenvironment has relatively high concentrations of adenosine.^[27] Recently, the role of the A2B receptor in the immune system has been demonstrated.^[28]^[29] Studies propose that in tissues where they are co-expressed, A2A and A2B form dimers under the majority control of the A2B receptor.^[30]
B7-H3: also called CD276, was originally understood to be a co-stimulatory molecule^[31] but is now regarded as co-inhibitory.^[32] The American biotechnology company MacroGenics is working on MGA271 is an Fc-optimized monoclonal antibody that targets B7-H3.^[33] B7-H3’s receptors have not yet been identified.^[34]
B7-H4: also called VTCN1, is expressed by tumor cells and tumor-associated macrophages and plays a role in tumour escape.^[35]
BTLA: This molecule, short for B and T Lymphocyte Attenuator and also called CD272, has HVEM (Herpesvirus Entry Mediator) as its ligand. Surface expression of BTLA is gradually downregulated during differentiation of human CD8+ T cells from the naive to effector cell phenotype, however tumor-specific human CD8+ T cells express high levels of BTLA.^[36]
CTLA-4: short for Cytotoxic T-Lymphocyte-Associated protein 4 and also called CD152, is the target of Bristol-Myers Squibb's melanoma drug Yervoy, which gained FDA approval in March 2011. Expression of CTLA-4 on Treg cells serves to control T cell proliferation.^[37]^[38]
IDO: short for Indoleamine 2,3-dioxygenase, is a tryptophan catabolic enzyme with immune-inhibitory properties. Another important molecule is TDO, tryptophan 2,3-dioxygenase. IDO is known to suppress T and NK cells, generate and activate Tregs and myeloid-derived suppressor cells, and promote tumour angiogenesis.^[39]^[38]
KIR: short for Killer-cell Immunoglobulin-like Receptor, is a receptor for MHC Class I molecules on Natural Killer cells. Bristol-Myers Squibb is working on Lirilumab, a monoclonal antibody to KIR.
LAG3: short for Lymphocyte Activation Gene-3, works to suppress an immune response by action to Tregs^[40] as well as direct effects on CD8+ T cells.^[41]^[38] Bristol-Myers Squibb is in Phase I with an anti-LAG3 monoclonal antibody called BMS-986016.^[42]
NOX2: short for nicotinamide adenine dinucleotide phosphate NADPH oxidase isoform 2, is an enzyme of myeloid cells that generates immunosuppressive reactive oxygen species. Genetic and pharmacological inhibition of NOX2 in myeloid cells improves anti-tumor functions of adjacent NK cells and T cells and also triggers autoimmunity in humans and experimental animals. NOX2 is the target of Ceplene that has gained approval for use in acute myeloid leukemia within the EU. ^[43]^[38]
PD-1: short for Programmed Death 1 (PD-1) receptor, has two ligands, PD-L1 and PD-L2. This checkpoint is the target of Merck & Co.'s melanoma drug Keytruda, which gained FDA approval in September 2014. The checkpoint is also the target of EMD Serono (Merck KGaA)'s drug Bavencio, which gained FDA approval in 2017. An advantage of targeting PD-1 is that it can restore immune function in the tumor microenvironment.^[44]^[38]
TIM-3: short for T-cell Immunoglobulin domain and Mucin domain 3, expresses on activated human CD4+ T cells and regulates Th1 and Th17 cytokines.^[45] TIM-3 acts as a negative regulator of Th1/Tc1 function by triggering cell death upon interaction with its ligand, galectin-9.^[46]^[38]
VISTA: Short for V-domain Ig suppressor of T cell activation, VISTA is primarily expressed on hematopoietic cells^[47] so that consistent expression of VISTA on leukocytes within tumors may allow VISTA blockade to be effective across a broad range of solid tumors.^[48]^[38]
SIGLEC7 (Sialic acid-binding immunoglobulin-type lectin 7, also designated as CD328) and SIGLEC9 (Sialic acid-binding immunoglobulin-type lectin 9, also designated as CD329) are proteins found on the surface of various immune cells, including natural killer cells and macrophages (SIGLEC7) and neutrophils, macrophages, dendritic cells and activated T-cells (SIGLEC9).^[49] SIGLECs 7 and 9 suppress the immune function of these cells by binding to terminal sialic acid on glycans that cover the surface of cells.^[50]^[51]

Immune checkpoint inhibitors

Drugs or drug candidates that inhibit/block the inhibitory checkpoint molecules are sometimes known as checkpoint inhibitors; this idea is often referred to as immune checkpoint blockade, or simply checkpoint blockade.^[52]^[38] Checkpoint inhibitor drugs have seen growth in pharmaceutical research in cancer by companies including Bristol-Myers Squibb, Merck, Merck KGaA, Roche and AstraZeneca.^[53]

Related Research Articles

Natural killer cells, also known as NK cells, are a type of cytotoxic lymphocyte critical to the innate immune system. They are a kind of large granular lymphocytes (LGL), and belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cells, stressed cells, tumor cells, and other intracellular pathogens based on signals from several activating and inhibitory receptors. Most immune cells detect the antigen presented on major histocompatibility complex I (MHC-I) on infected cell surfaces, but NK cells can recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology (immuno-oncology) and a growing subspecialty of oncology.

Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on T_H cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.

Co-stimulation is a secondary signal which immune cells rely on to activate an immune response in the presence of an antigen-presenting cell. In the case of T cells, two stimuli are required to fully activate their immune response. During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.

Tumor necrosis factor receptor superfamily, member 4 (TNFRSF4), also known as CD134 and OX40 receptor, is a member of the TNFR-superfamily of receptors which is not constitutively expressed on resting naïve T cells, unlike CD28. OX40 is a secondary co-stimulatory immune checkpoint molecule, expressed after 24 to 72 hours following activation; its ligand, OX40L, is also not expressed on resting antigen presenting cells, but is following their activation. Expression of OX40 is dependent on full activation of the T cell; without CD28, expression of OX40 is delayed and of fourfold lower levels.

CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophils, monocytes, macrophages, and certain T cells. CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRIIIb (CD16b), which participate in signal transduction. The most well-researched membrane receptor implicated in triggering lysis by NK cells, CD16 is a molecule of the immunoglobulin superfamily (IgSF) involved in antibody-dependent cellular cytotoxicity (ADCC). It can be used to isolate populations of specific immune cells through fluorescent-activated cell sorting (FACS) or magnetic-activated cell sorting, using antibodies directed towards CD16.

Tumor necrosis factor ligand superfamily member 9 also known as 4-1BB ligand or 4-1BBL or CD137L is a protein that in humans is encoded by the TNFSF9 gene.

CD137, a member of the tumor necrosis factor (TNF) receptor family, is a type 1 transmembrane protein, expressed on surfaces of leukocytes and non-immune cells. Its alternative names are tumor necrosis factor receptor superfamily member 9 (TNFRSF9), 4-1BB, and induced by lymphocyte activation (ILA). It is of interest to immunologists as a co-stimulatory immune checkpoint molecule, and as a potential target in cancer immunotherapy.

CD27 is a member of the tumor necrosis factor receptor superfamily. It is currently of interest to immunologists as a co-stimulatory immune checkpoint molecule, and is the target of an anti-cancer drug in clinical trials.

Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.

Programmed cell death protein 1(PD-1),. PD-1 is a protein encoded in humans by the PDCD1 gene. PD-1 is a cell surface receptor on T cells and B cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.

Programmed cell death 1 ligand 2 is a protein that in humans is encoded by the PDCD1LG2 gene. PDCD1LG2 has also been designated as CD273. PDCD1LG2 is an immune checkpoint receptor ligand which plays a role in negative regulation of the adaptive immune response. PD-L2 is one of two known ligands for Programmed cell death protein 1 (PD-1).

Hepatitis A virus cellular receptor 2 (HAVCR2), also known as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), is a protein that in humans is encoded by the HAVCR2 (TIM-3) gene. HAVCR2 was first described in 2002 as a cell surface molecule expressed on IFNγ producing CD4+ Th1 and CD8+ Tc1 cells. Later, the expression was detected in Th17 cells, regulatory T-cells, and innate immune cells. HAVCR2 receptor is a regulator of the immune response.

Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced TNFR-related protein (GITR) or CD357. GITR is encoded and tnfrsf18 gene at chromosome 4 in mice. GITR is type I transmembrane protein and is described in 4 different isoforms. GITR human orthologue, also called activation-inducible TNFR family receptor (AITR), is encoded by the TNFRSF18 gene at chromosome 1.

CD160 antigen is a protein that in humans is encoded by the CD160 gene.

Urelumab is a fully human, non‐ligand binding, CD137 agonist immunoglobulin‐γ 4 (IgG4) monoclonal antibody. It was developed utilizing Medarex's UltiMAb(R) technology by Bristol-Myers Squibb for the treatment of cancer and solid tumors. Urelumab promotes anti-tumor immunity, or an immune response against tumor cells, via CD137 activation. The application of Urelumab has been limited because it can cause severe liver toxicity.

V-domain Ig suppressor of T cell activation (VISTA) is a type I transmembrane protein that functions as an immune checkpoint and is encoded by the VSIR gene.

CD28 family receptors are a group of regulatory cell surface receptors expressed on immune cells. The CD28 family in turn is a subgroup of the immunoglobulin superfamily.

APC Activators are a type of immunotherapy which leverages antigen-presenting cells (APCs) to drive an adaptive immune response. APC Activators are agonists to APC surface-expressed ligands that, when bound, induce the maturation and activation of APCs. Professional antigen-presenting cells – including dendritic cells, macrophages, and B cells – serve an indispensable role in the adaptive immune response through their unique ability to phagocytose, digest, and present exogenous (circulating) antigens to T cells, facilitating antigen-specific immune responses.

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↑ Lines JL, Pantazi E, Mak J, Sempere LF, Wang L, O'Connell S, et al. (April 2014). "VISTA is an immune checkpoint molecule for human T cells". Cancer Research. 74 (7): 1924–1932. doi:10.1158/0008-5472.CAN-13-1504. PMC 3979527 . PMID 24691993.
↑ Stanczak MA, Siddiqui SS, Trefny MP, Thommen DS, Boligan KF, von Gunten S, et al. (November 2018). "Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells". The Journal of Clinical Investigation. 128 (11): 4912–4923. doi:10.1172/JCI120612. PMC 6205408 . PMID 30130255.
↑ Crocker PR, Paulson JC, Varki A (April 2007). "Siglecs and their roles in the immune system". Nature Reviews. Immunology. 7 (4): 255–266. doi: 10.1038/nri2056 . PMID 17380156. S2CID 26722878.
↑ Macauley MS, Crocker PR, Paulson JC (October 2014). "Siglec-mediated regulation of immune cell function in disease". Nature Reviews. Immunology. 14 (10): 653–666. doi:10.1038/nri3737. PMC 4191907 . PMID 25234143.
↑ Pardoll DM (March 2012). "The blockade of immune checkpoints in cancer immunotherapy". Nature Reviews. Cancer. 12 (4): 252–264. doi:10.1038/nrc3239. PMC 4856023 . PMID 22437870.
↑ "Cancer drugs are getting better and dearer". The Economist. 2017-05-04. Retrieved 2017-05-19.

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