Cancer immunology is an interdisciplinary branch of
biology
Biology is the scientific study of life. It is a natural science with a broad scope but has several unifying themes that tie it together as a single, coherent field. For instance, all organisms are made up of cells that process hereditary i ...
that is concerned with understanding the role of 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 ...
in the progression and development 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 ...
; the most well known application is
cancer immunotherapy
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 im ...
, which utilises the immune system as a treatment for cancer. Cancer
immunosurveillance
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 splinters, ...
and
immunoediting Immunoediting is a dynamic process that consists of immunosurveillance and tumor progression. It describes the relation between the tumor cells and the immune system. It is made up of three phases: ''elimination'', ''equilibrium'', and ''escape''.
...
are based on protection against development of tumors in animal systems and (ii) identification of targets for immune recognition of human cancer.
Definition
Cancer immunology is an interdisciplinary branch of biology concerned with the role of 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 ...
in the progression and development 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 ...
; the most well known application is
cancer immunotherapy
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 im ...
, where the immune system is used to treat cancer.
Cancer
immunosurveillance
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 splinters, ...
is a theory formulated in 1957 by Burnet and Thomas, who proposed that
lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
s act as sentinels in recognizing and eliminating continuously arising, nascent
transformed cells.
Cancer immunosurveillance appears to be an important host protection process that decreases cancer rates through inhibition of
carcinogenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
and maintaining of regular cellular
homeostasis
In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
.
It has also been suggested that immunosurveillance primarily functions as a component of a more general process of cancer immunoediting.
Tumor antigens
Tumors may express tumor antigens that are recognized by the immune system and may induce an immune response. These tumor antigens are either TSA (Tumor-specific antigen) or TAA (Tumor-associated antigen).
Tumor-specific
Tumor-specific antigens (TSA) are antigens that only occur in tumor cells.
TSAs can be products of oncoviruses like E6 and E7 proteins of
human papillomavirus
Human papillomavirus infection (HPV infection) is caused by a DNA virus from the ''Papillomaviridae'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and res ...
, occurring in
cervical carcinoma
Cervical cancer is a cancer arising from the cervix. It is due to the abnormal growth of cells that have the ability to invade or spread to other parts of the body. Early on, typically no symptoms are seen. Later symptoms may include abnormal ...
, or EBNA-1 protein of
EBV, occurring in
Burkitt's lymphoma
Burkitt lymphoma is a cancer of the lymphatic system, particularly B lymphocytes found in the germinal center. It is named after Denis Parsons Burkitt, the Irish surgeon who first described the disease in 1958 while working in equatorial Africa. ...
cells. Another example of TSAs are abnormal products of mutated oncogenes (e.g.
Ras protein
Ras, from "Rat sarcoma virus", is a family of related proteins that are expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals ...
) and anti-oncogenes (e.g.
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
).
Tumor-associated antigens
Tumor-associated antigens (TAA) are present in healthy cells, but for some reason they also occur in tumor cells.
However, they differ in quantity, place or time period of expression. Oncofetal antigens are tumor-associated antigens expressed by embryonic cells and by tumors. Examples of oncofetal antigens are
AFP (α-fetoprotein), produced by
hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide.
It occurs in t ...
, or
CEA (carcinoembryonic antigen), occurring in ovarian and colon cancer. More tumor-associated antigens are HER2/neu, EGFR or MAGE-1.
Immunoediting
Cancer
immunoediting Immunoediting is a dynamic process that consists of immunosurveillance and tumor progression. It describes the relation between the tumor cells and the immune system. It is made up of three phases: ''elimination'', ''equilibrium'', and ''escape''.
...
is a process in which
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 ...
interacts with tumor cells. It consists of three phases: elimination, equilibrium and escape. These phases are often referred to as "the three Es" of cancer immunoediting. Both
adaptive
Adaptation, in biology, is the process or trait by which organisms or population better match their environment
Adaptation may also refer to:
Arts
* Adaptation (arts), a transfer of a work of art from one medium to another
** Film adaptation, a ...
and
innate immune system
The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
participate in immunoediting.
In the elimination phase, the immune response leads to destruction of tumor cells and therefore to tumor suppression. However, some tumor cells may gain more mutations, change their characteristics and evade the immune system. These cells might enter the equilibrium phase, in which the immune system does not recognise all tumor cells, but at the same time the tumor does not grow. This condition may lead to the phase of escape, in which the tumor gains dominance over immune system, starts growing and establishes immunosuppressive environment.
As a consequence of immunoediting, tumor cell clones less responsive to the immune system gain dominance in the tumor through time, as the recognized cells are eliminated. This process may be considered akin to Darwinian evolution, where cells containing pro-oncogenic or immunosuppressive mutations survive to pass on their mutations to daughter cells, which may themselves mutate and undergo further selective pressure. This results in the tumor consisting of cells with decreased
immunogenicity
Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted:
* Wanted immunogenicity typically relates to vaccines, where the injectio ...
and can hardly be eliminated.
This phenomenon was proven to happen as a result of
immunotherapies
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 immunotherap ...
of cancer patients.
Tumor evasion mechanisms
![Tumor microenvironment](https://upload.wikimedia.org/wikipedia/commons/0/04/Tumor_microenvironment.jpg)
*
CD8+ cytotoxic T cells are a fundamental element of anti-tumor immunity. Their
TCR receptors recognise antigens presented by
MHC class I
MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II) and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on plat ...
and when bound, the Tc cell triggers its
cytotoxic
Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa'').
Cell physiology
Treating cells ...
activity. MHC I are present on the surface of all nucleated cells. However, some cancer cells lower their MHC I expression and avoid being detected by the cytotoxic T cells.
This can be done by mutation of MHC I gene or by lowering the sensitivity to IFN-γ (which influences the surface expression of MHC I).
Tumor cells also have defects in antigen presentation pathway, what leads into down-regulation of tumor antigen presentations. Defects are for example in
transporter associated with antigen processing
Transporter associated with antigen processing (TAP) protein complex belongs to the ATP-binding-cassette transporter family. It delivers cytosolic peptides into the endoplasmic reticulum (ER), where they bind to nascent MHC class I molecules.
...
(TAP) or
tapasin
TAP-associated glycoprotein, also known as tapasin or TAPBP, is a protein that in humans is encoded by the ''TAPBP'' gene.
Function
The ''TAPBP'' gene encodes a transmembrane glycoprotein that mediates interaction between newly assembled maj ...
. On the other hand, a complete loss of MHC I is a trigger for
NK cells
Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...
.
Tumor cells therefore maintain a low expression of MHC I.
* Another way to escape cytotoxic T cells is to stop expressing molecules essential for co-stimulation of cytotoxic T cells, such as
CD80
The Cluster of differentiation 80 (also CD80 and B7-1) is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is cl ...
or
CD86
Cluster of Differentiation 86 (also known as CD86 and B7-2) is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells (including memory B-cells), and on other antigen-presenting cells. Along with CD80, CD ...
.
*Tumor cells express molecules to induce apoptosis or to inhibit
T lymphocytes
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 rec ...
:
** Expression of
FasL
Fas ligand (FasL or CD95L or CD178) is a type-II transmembrane protein that belongs to the tumor necrosis factor (TNF) family. Its binding with its receptor induces apoptosis. Fas ligand/receptor interactions play an important role in the regula ...
on its surface, tumor cells may induce
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 ...
of T lymphocytes by FasL-Fas interaction.
** Expression of
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 ...
on the surface of tumor cells leads to suppression of T lymphocytes by
PD1-PD-L1 interaction.
* Tumor cells have gained resistance to effector mechanisms of
NK and
cytotoxic CD8+ T cell:
** by loss of gene expression or inhibition of apoptotic signal pathway molecules:
APAF1
Apoptotic protease activating factor 1, also known as APAF1, is a human homolog of ''C. elegans'' CED-4 gene.
Function
The protein was identified in the lab of Xiaodong Wang as an activator of caspase-3 in the presense of cytochromeC and dATP ...
,
Caspase 8
Caspase-8 is a caspase protein, encoded by the ''CASP8'' gene. It most likely acts upon caspase-3.
''CASP8'' orthologs have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also prese ...
,
Bcl-2-associated X protein
Apoptosis regulator BAX, also known as bcl-2-like protein 4, is a protein that in humans is encoded by the ''BAX'' gene. ''BAX'' is a member of the Bcl-2 gene family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apopto ...
(bax) and
Bcl-2 homologous antagonist killer
Bcl-2 homologous antagonist/killer is a protein that in humans is encoded by the ''BAK1'' gene on chromosome 6. The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form oligomers or heterodimers and act as ant ...
(bak).
** by induction of expression or overexpression of antiapoptotic molecules:
Bcl-2
Bcl-2 (B-cell lymphoma 2), encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosis. ...
,
IAP or
XIAP
X-linked inhibitor of apoptosis protein (XIAP), also known as inhibitor of apoptosis protein 3 (IAP3) and baculoviral IAP repeat-containing protein 4 (BIRC4), is a protein that stops apoptotic cell death. In humans, this protein (XIAP) is produ ...
.
Tumor microenvironment
![Immune checkpoints of immunosuppressive actions associated with breast cancer](https://upload.wikimedia.org/wikipedia/commons/f/fa/Immune_checkpoints_of_immunosuppressive_actions_associated_with_breast_cancer.svg)
* Production of
TGF-β
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...
by tumor cells and other cells (such as
myeloid-derived suppressor cell) leads to conversion of
CD4+ T cell
In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic ...
into suppressive
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 immunosup ...
(Treg) by a contact dependent or independent stimulation. In a healthy tissue, functioning Tregs are essential to maintain self-tolerance. In a tumor, however, Tregs form an immunosuppressive microenviroment.
* Tumor cells produce special cytokines (such as
colony-stimulating factor
Colony-stimulating factors (CSFs) are secreted glycoproteins that bind to receptor proteins on the surfaces of hemopoietic stem cells, thereby activating intracellular signaling pathways that can cause the cells to proliferate and differentia ...
) to produce
myeloid-derived suppressor cell. These cells are heterogenous collection of cel
l types including
precursors of
dendritic cell
Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. ...
,
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also inf ...
and
neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
. MDSC have suppressive effects on
T-lymphocyte
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 rec ...
s, dendritic 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. They produce immunosuppressive
TGF-β
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...
and
IL-10.
*Another producer of suppressive
TGF- β and
IL-10 are
tumor-associated macrophage Tumor-associated macrophages (TAMs) are a class of immune cells present in high numbers in the microenvironment of solid tumors. They are heavily involved in cancer-related inflammation. Macrophages are known to originate from bone marrow-derived bl ...
s, these macrophages have mostly phenotype of alternatively activated
M2 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.
Their activation
is promoted by
TH type 2 cytokines (such as
IL-4 and
IL-13). Their main effects are immunosuppression, promotion of tumor growth and
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
.
*Tumor cells have
non-classical MHC class I on their surface, for example
HLA-G
HLA-G histocompatibility antigen, class I, G, also known as human leukocyte antigen G (HLA-G), is a protein that in humans is encoded by the ''HLA-G'' gene.
HLA-G belongs to the HLA nonclassical class I heavy chain paralogues. Classical HLA I pro ...
. HLA-G is inducer of Treg, MDSC, polarise macrophages into alternatively activated M2 and has other immunosuppressive effects on immune cells.
Immunomodulation methods
Immune system is the key player in fighting cancer. As described above in mechanisms of tumor evasion, the tumor cells are modulating the immune response in their profit. It is possible to improve the immune response in order to boost the immunity against tumor cells.
*monoclonal anti-
CTLA4
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 expres ...
and anti-
PD-1
Programmed cell death protein 1, also known as PD-1 and CD279 (cluster of differentiation 279), is a protein on the surface of T and B cells that has a role in regulating the immune system's response to the cells of the human body by down-regula ...
antibodies are called
immune checkpoint 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 im ...
s:
**CTLA-4 is a receptor upregulated on the membrane of activated T lymphocytes, CTLA-4
CD80
The Cluster of differentiation 80 (also CD80 and B7-1) is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is cl ...
/
86 interaction leads to switch off of T lymphocytes. By blocking this interaction with monoclonal anti CTLA-4 antibody we can increase the immune response. An example of approved drug is
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 recognize ...
.
**PD-1 is also an upregulated receptor on the surface of T lymphocytes after activation. Interaction PD-1 with
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 ...
leads to switching off or
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 ...
. PD-L1 are molecules which can be produced by tumor cells. The monoclonal anti-PD-1 antibody is blocking this interaction thus leading to improvement of immune response in CD8+ T lymphocytes. An example of approved cancer drug is
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 ...
.
**
Chimeric Antigen Receptor T cell
In biology, chimeric antigen receptors (CARs)—also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors—are receptor proteins that have been engineered to give T cells the new ability to target a specific ...
***This CAR receptors are genetically engineered receptors with extracellular tumor specific binding sites and intracelullar signalling domain that enables the T lymphocyte activation.
**
Cancer vaccine
A cancer vaccine is a vaccine that either treats existing cancer or prevents development of cancer. Vaccines that treat existing cancer are known as ''therapeutic'' cancer vaccines or tumor antigen vaccines. Some of the vaccines are "autologous", ...
***Vaccine can be composed of killed tumor cells, recombinant tumor antigens, or dendritic cells incubated with tumor antigens (
dendritic cell-based cancer vaccine The dendritic cell-based cancer vaccine is an innovation in therapeutic strategy for cancer patients.
Dendritic cells (DCs) are antigen presenting cells for the induction of antigen specific T cell response. DC-based immunotherapy is safe and can ...
)
Relationship to chemotherapy
Obeid et al.
investigated how inducing immunogenic cancer cell death ought to become a priority of cancer chemotherapy. He reasoned, the immune system would be able to play a factor via a 'bystander effect' in eradicating chemotherapy-resistant cancer cells.
However, extensive research is still needed on how the immune response is triggered against dying tumour cells.
Professionals in the field have hypothesized that 'apoptotic cell death is poorly immunogenic whereas
necrotic cell death is truly immunogenic'.
This is perhaps because cancer cells being eradicated via a necrotic cell death pathway induce an immune response by triggering dendritic cells to mature, due to inflammatory response stimulation.
On the other hand, apoptosis is connected to slight alterations within the plasma membrane causing the dying cells to be attractive to phagocytic cells.
However, numerous animal studies have shown the superiority of vaccination with apoptotic cells, compared to necrotic cells, in eliciting anti-tumor immune responses.
Thus Obeid ''et al.''
propose that the way in which cancer cells die during chemotherapy is vital.
Anthracyclins produce a beneficial immunogenic environment. The researchers report that when killing cancer cells with this agent uptake and presentation by antigen presenting dendritic cells is encouraged, thus allowing a T-cell response which can shrink tumours. Therefore, activating tumour-killing T-cells is crucial for immunotherapy success.
However, advanced cancer patients with immunosuppression have left researchers in a dilemma as to how to activate their T-cells. The way the host dendritic cells react and uptake tumour antigens to present to CD4
+ and CD8
+ T-cells is the key to success of the treatment.
See also
*
Oncogenomics
Oncogenomics is a sub-field of genomics that characterizes cancer-associated genes. It focuses on genomic, epigenomic and transcript alterations in cancer.
Cancer is a genetic disease caused by accumulation of DNA mutations and epigenetic alte ...
References
{{DEFAULTSORT:Cancer Immunology
Oncology
Branches of immunology