Programmed cell death protein 1, also known as PD-1 and CD279 (
cluster of differentiation
The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophen ...
279), is a
protein on the surface of T and B cells that has a role in regulating the
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
inflammatory activity. This prevents
autoimmune diseases, but it can also prevent the immune system from killing cancer cells.
PD-1 is an
immune checkpoint
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 stimula ...
and guards against autoimmunity through two mechanisms. First, it promotes
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
(programmed cell death) of
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
-specific T-cells in
lymph node
A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that inclu ...
s. Second, it reduces apoptosis in
regulatory T cell
The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosu ...
s (anti-inflammatory, suppressive T cells).
PD-1 inhibitor
Cancer immunotherapy (sometimes called immuno-oncology) is the stimulation of the immune system to treat cancer, improving on the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer ...
s, a new class of drugs that block PD-1, activate the immune system to attack tumors and are used to treat certain types of cancer.
The PD-1
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
in humans is encoded by the ''PDCD1''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
PD-1 is a cell surface
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
that belongs to the
immunoglobulin superfamily
The immunoglobulin superfamily (IgSF) is a large protein superfamily of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily ...
and is expressed on
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s and pro-
B cells.
PD-1 binds two
ligands
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...
,
PD-L1
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 death-ligand 1 (PD-L1) is a 40kDa type 1 transmembrane protei ...
and
PD-L2.
Discovery
In a screen for genes involved in
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, Yasumasa Ishida,
Tasuku Honjo
is a Japanese physician-scientist and immunologist. He won the 2018 Nobel Prize in Physiology or Medicine and is best known for his identification of programmed cell death protein 1 (PD-1).
He is also known for his molecular identification o ...
and colleagues at
Kyoto University
, mottoeng = Freedom of academic culture
, established =
, type = National university, Public (National)
, endowment = ¥ 316 billion (2.4 1000000000 (number), billion USD)
, faculty = 3,480 (Teaching Staff)
, administrative_staff ...
in 1992 discovered and named PD-1.
In 1999, the same group demonstrated that mice where PD-1 was knocked down were prone to autoimmune disease and hence concluded that PD-1 was a negative regulator of immune responses.
Structure
PD-1 is a type I
membrane protein
Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...
of 288
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s. PD-1 is a member of the extended
CD28/
CTLA-4
CTLA-4 or CTLA4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 ( cluster of differentiation 152), is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA-4 is constitutively exp ...
family of
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
regulators.
The protein's structure includes an extracellular
IgV domain followed by a
transmembrane
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequent ...
region and an intracellular tail. The intracellular tail contains two
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
sites located in an
immunoreceptor tyrosine-based inhibitory motif An immunoreceptor tyrosine-based inhibitory motif (ITIM), is a conserved sequence of amino acids that is found intracellularly in the cytoplasmic domains of many inhibitory receptors of the non-catalytic tyrosine-phosphorylated receptor family fou ...
and an immunoreceptor tyrosine-based switch motif, which suggests that PD-1 negatively regulates T-cell receptor
TCR signals.
This is consistent with binding of
SHP-1
Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the ''PTPN6'' gene.
Function
The protein encoded by this gene is a member ...
and
SHP-2
Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in huma ...
phosphatases to the cytoplasmic tail of PD-1 upon ligand binding. In addition, PD-1 ligation up-regulates E3-ubiquitin ligases
CBL-b and c-CBL that trigger T cell receptor down-modulation.
PD-1 is expressed on the surface of activated T cells,
B cells, and
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s,
suggesting that compared to CTLA-4, PD-1 more broadly negatively regulates immune responses.
Ligands
PD-1 has two
ligands
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...
,
PD-L1
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 death-ligand 1 (PD-L1) is a 40kDa type 1 transmembrane protei ...
and
PD-L2, which are members of the
B7 family.
PD-L1 protein is upregulated on macrophages and
dendritic cells (DC) in response to
LPS and
GM-CSF
Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts tha ...
treatment, and on T cells and B cells upon TCR and B cell receptor signaling, whereas in resting mice, PD-L1
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
can be detected in the heart, lung, thymus, spleen, and kidney.
PD-L1 is expressed on almost all murine tumor cell lines, including PA1 myeloma, P815 mastocytoma, and B16 melanoma upon treatment with
IFN-γ
Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
.
PD-L2 expression is more restricted and is expressed mainly by DCs and a few tumor lines.
Function
Several lines of evidence suggest that PD-1 and its ligands negatively regulate immune responses. PD-1
knockout mice have been shown to develop lupus-like
glomerulonephritis
Glomerulonephritis (GN) is a term used to refer to several kidney diseases (usually affecting both kidneys). Many of the diseases are characterised by inflammation either of the glomeruli or of the small blood vessels in the kidneys, hence the ...
and dilated
cardiomyopathy
Cardiomyopathy is a group of diseases that affect the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...
on the C57BL/6 and BALB/c backgrounds, respectively.
In vitro, treatment of anti-
CD3 stimulated T cells with PD-L1-Ig results in reduced T cell proliferation and IFN-γ secretion.
IFN-γ is a key pro-inflammatory cytokine that promotes T cell inflammatory activity. Reduced T cell proliferation was also correlated with attenuated IL-2 secretion and together, these data suggest that PD-1 negatively regulates T cell responses.
Experiments using PD-L1 transfected DCs and PD-1 expressing transgenic (Tg)
CD4+ and
CD8+ T cells suggest that CD8
+ T cells are more susceptible to inhibition by PD-L1, although this could be dependent on the strength of TCR signaling. Consistent with a role in negatively regulating CD8
+ T cell responses, using an
LCMV
Lymphocytic choriomeningitis (LCM) is a rodent-borne viral infectious disease that presents as aseptic meningitis, encephalitis or meningoencephalitis. Its causative agent is ''lymphocytic choriomeningitis mammarenavirus'' (LCMV), a member of th ...
viral vector model of chronic infection, Rafi Ahmed's group showed that the PD-1-PD-L1 interaction inhibits activation, expansion and acquisition of effector functions of virus specific CD8
+ T cells, which can be reversed by blocking the PD-1-PD-L1 interaction.
Expression of PD-L1 on tumor cells inhibits anti-tumor activity through engagement of PD-1 on effector T cells.
Expression of PD-L1 on tumors is correlated with reduced survival in esophageal, pancreatic and other types of cancers, highlighting this pathway as a target for immunotherapy.
Triggering PD-1, expressed on monocytes and up-regulated upon monocytes activation, by its ligand PD-L1 induces IL-10 production which inhibits CD4 T-cell function.
In mice, expression of this gene is induced in the thymus when anti-
CD3 antibodies are injected and large numbers of
thymocyte
A Thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood. Thymopoiesis describes the process which turns thymo ...
s undergo
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
. Mice deficient for this gene bred on a BALB/c background developed
dilated cardiomyopathy
Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively. Symptoms vary from none to feeling tired, leg swelling, and shortness of breath. It may also result in chest pain or fainting. Co ...
and died from
congestive heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...
. These studies suggest that this gene product may also be important in
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
function and contribute to the prevention of
autoimmune diseases.
Overexpression of PD1 on CD8+ T cells is one of the indicators of
T-cell exhaustion
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
(e.g. in chronic infection or cancer).
Clinical significance
Cancer
PD-L1, the ligand for PD1, is highly expressed in several cancers and hence the role of PD1 in cancer immune evasion is well established.
Monoclonal antibodies targeting PD-1 that boost the
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
are being developed for the treatment of
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
.
Many tumor cells express PD-L1, an immunosuppressive PD-1 ligand; inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responses ''in vitro'' and mediate preclinical antitumor activity. This is known as
immune checkpoint blockade
Cancer immunotherapy (sometimes called immuno-oncology) is the stimulation of the immune system to treat cancer, improving on the immune system's natural ability to fight the disease. It is an application of the basic research, fundamental resea ...
.
Combination therapy using both anti-PD1 along with anti-
CTLA4 therapeutics have emerged as important tumor treatments within the field of
checkpoint inhibition
Checkpoint inhibitor therapy is a form of cancer immunotherapy. The therapy targets immune checkpoints, key regulators of the immune system that when stimulated can dampen the immune response to an immunologic stimulus. Some cancers can protect th ...
.
A combination of PD1 and CTLA4 antibodies has been shown to be more effective than either antibody alone in the treatment of a variety of cancers. The effects of the two antibodies do not appear to be redundant.
Anti-CTLA4 treatment leads to an enhanced antigen specific T cell dependent immune reaction while anti-PD-1 appears to reactivate
CD8+ T cells
A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pa ...
ability to lyse cancer cells.
In clinical trials, combination therapy has been shown to be effective in reducing tumor size in patients that are unresponsive to single co-inhibitory blockade, despite increasing levels of toxicity due to anti-CTLA4 treatment.
A combination of PD1 and CTLA4 induced up to a ten-fold higher number of CD8+ T cells that are actively infiltrating the tumor tissue.
The authors hypothesized that the higher levels of CD8+ T cell infiltration was due to anti-CTLA-4 inhibited the conversion of CD4 T cells to T regulator cells and further reduced T regulatory suppression with anti-PD-1. This combination promoted a more robust inflammatory response to the tumor that reduced the size of the cancer. Most recently, the FDA has approved a combination therapy with both anti-CTLA4 (
ipilimumab
Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.
Cytotoxic T lymphocytes (CTLs) can recogniz ...
) and anti-PD1 (
nivolumab
Nivolumab, sold under the brand name Opdivo, is a medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urotheli ...
) in October 2015.
The molecular factors and receptors necessary making a tumor receptive to anti-PD1 treatment remains unknown.
PD-L1
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 death-ligand 1 (PD-L1) is a 40kDa type 1 transmembrane protei ...
expression on the surface on cancer cells plays a significant role. PD-L1 positive tumors were twice as likely to respond to combination treatment.
However patients with PD-L1 negative tumors also have limited response to anti-PD1, demonstrating that PD-L1 expression is not an absolute determinant of the effectiveness of therapy.
Higher mutational burden in the tumor is correlated with a greater effect of the anti-PD-1 treatment. In clinical trials, patients who benefited from anti-PD1 treatment had cancers, such as melanoma, bladder cancer, and gastric cancer, that had a median higher average number of mutations than the patients who did not respond to the therapy. However, the correlation between higher tumor burden and the clinical effectiveness of PD-1 immune blockade is still uncertain.
The 2018 Nobel prize for medicine was awarded to
James P Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation".
Anti-PD-1 therapeutics
A number of cancer immunotherapy agents that target the PD-1 receptor have been developed.
One such anti-PD-1 antibody drug,
nivolumab
Nivolumab, sold under the brand name Opdivo, is a medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urotheli ...
, (Opdivo -
Bristol-Myers Squibb
The Bristol Myers Squibb Company (BMS) is an American multinational pharmaceutical company. Headquartered in New York City, BMS is one of the world's largest pharmaceutical companies and consistently ranks on the ''Fortune'' 500 list of the lar ...
), produced complete or partial responses in non-small-cell lung cancer, melanoma, and renal-cell cancer, in a clinical trial with a total of 296 patients.
[
*] Colon and pancreatic cancer did not have a response.
Nivolumab
Nivolumab, sold under the brand name Opdivo, is a medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urotheli ...
(Opdivo, Bristol-Myers Squibb) was approved in Japan in July 2014 and by the US FDA in December 2014 to treat metastatic
melanoma
Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
.
Pembrolizumab
Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast canc ...
(Keytruda, MK-3475, Merck), which also targets PD-1 receptors, was approved by the FDA in Sept 2014 to treat metastatic
melanoma
Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
. Pembrolizumab has been made accessible to advanced melanoma patients in the UK via UK Early Access to Medicines Scheme (EAMS) in March 2015. It is being used in clinical trials in the US for lung cancer, lymphoma, and mesothelioma. It has had measured success, with little side effects.
It is up to the manufacturer of the drug to submit application to the FDA for approval for use in these diseases. On October 2, 2015 Pembrolizumab was approved by FDA for advanced (metastatic) non-small cell lung cancer (NSCLC) patients whose disease has progressed after other treatments.
Other drugs in early stage development targeting PD-1 receptors (
checkpoint inhibitor
Checkpoint inhibitor therapy is a form of cancer immunotherapy. The therapy targets immune checkpoints, key regulators of the immune system that when stimulated can dampen the immune response to an immunologic stimulus. Some cancers can protect the ...
s) are
Pidilizumab (CT-011, Cure Tech),
BMS-936559 (Bristol Myers Squibb) and Toripalimab (JS-001
TopAlliance, a humanized IgG4 monoclonal antibody against PD-1. Both
Atezolizumab
Atezolizumab, sold under the brand name Tecentriq, is a monoclonal antibody medication used to treat urothelial carcinoma, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), small cell lung cancer (SCLC), hepatocellula ...
(MPDL3280A, Roche) and
Avelumab
Avelumab, sold under the brand name Bavencio, is a fully human monoclonal antibody medication for the treatment of Merkel cell carcinoma, urothelial carcinoma, and renal cell carcinoma.
Common side effects include fatigue, musculoskeletal pain, ...
(
Merck KGaA, Darmstadt, Germany &
Pfizer
Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfizer ...
) target the similar PD-L1 receptor.
Animal studies
HIV
Drugs targeting PD-1 in combination with other negative immune checkpoint receptors, such as (
TIGIT
TIGIT ( ; also called T cell immunoreceptor with Ig and ITIM domains) is an immune receptor present on some T cells and natural killer cells (NK). It is also identified as WUCAM and Vstm3. TIGIT could bind to CD155 (PVR) on dendritic cells (DCs) ...
), may augment immune responses and/or facilitate
HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
eradication.
T lymphocytes exhibit elevated expression of PD-1 in cases of chronic HIV infection.
Heightened presence of the PD-1 receptors corresponds to exhaustion of the HIV specific CD8+ cytotoxic and CD4+ helper T cell populations that are vital in combating the virus. Immune blockade of PD-1 resulted in restoration of T cell inflammatory phenotype necessary to combat the progression of disease.
Alzheimer's disease
Blocking of PD-1 leads to a reduction in cerebral amyloid-β plaques and improves cognitive performance in mice.
Immune blockade of PD-1 evoked an IFN-γ dependent immune response that recruited monocyte-derived macrophages to the brain that were then capable of clearing the amyloid-β plaques from the tissue. Repeated administrations with anti-PD-1 were found to be necessary to maintain the therapeutic effects of the treatment. Amyloid fibrils are immunosuppressive and this finding has been separately confirmed by examining the effects of the fibrils in neuroinflammatory diseases.
PD-1 counteracts the effects of the fibrils by boosting immune activity and triggering an immune pathway that allows for brain repair.
References
Further reading
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External links
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{{CD28 family receptors
What I Talk about When I Talk about the Discovery of PD-1 (Yasumasa Ishida)
Clusters of differentiation
Immune system