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 ...
that is concerned with understanding the role of the
immune system in the progression and development of
cancer; 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 ...
, which utilises the immune system as a treatment for cancer. Cancer
immunosurveillance 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 in the progression and development of
cancer; 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 ...
, where the immune system is used to treat cancer.
Cancer
immunosurveillance 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 adap ...
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 also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and i ...
.
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, 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 ...
).
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, 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 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 and
innate immune system 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 and can hardly be eliminated.
This phenomenon was proven to happen as a result of
immunotherapies of cancer patients.
Tumor evasion mechanisms
*
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 pla ...
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 cel ...
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.
T ...
(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 m ...
. On the other hand, a complete loss of MHC I is a trigger for
NK cells.
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, CD8 ...
.
*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 regulati ...
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 includ ...
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 prote ...
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 present ...
,
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-apopt ...
(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 a ...
(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.
Tumor microenvironment
* 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 s ...
by tumor cells and other cells (such as
myeloid-derived suppressor cell
Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immune cells from the myeloid lineage (a family of cells that originate from bone marrow stem cells).
MDSCs expand under pathologic conditions such as chronic infection and cance ...
) leads to conversion of
CD4+ T cell
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
into suppressive
regulatory T cell (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
Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immune cells from the myeloid lineage (a family of cells that originate from bone marrow stem cells).
MDSCs expand under pathologic conditions such as chronic infection and cance ...
. These cells are heterogenous collection of cel
l types including
precursors of
dendritic cell,
monocyte and
neutrophil. 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 r ...
s, dendritic cells and
macrophages. 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 s ...
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 ce ...
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 splittin ...
.
*Tumor cells have
non-classical MHC class I on their surface, for example
HLA-G. 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 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 recogni ...
.
**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 prote ...
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 includ ...
. 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.
**
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 specif ...
***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.
Anthracyclin
Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from ''Streptomyces'' bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder can ...
s 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