Cancer immunology
Encyclopedia
Cancer immunology is the study of interactions between the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

 and cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

 cells (also called tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...

s or malignancies). It is also a growing field of research that aims to discover innovative cancer immunotherapies
Immunotherapy
Immunotherapy is a medical term defined as the "treatment of disease by inducing, enhancing, or suppressing an immune response". Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies. While immunotherapies that reduce or suppress are...

 to treat and retard progression of this disease. The immune response, including the recognition of cancer-specific antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...

s is of particular interest in this field as knowledge gained drives the development of new vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...

s and antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...

 therapies. For instance in 2007, Ohtani published a paper finding tumour infiltrating lymphocytes to be quite significant in human colorectal cancer. The host was given a better chance at survival if the cancer tissue showed infiltration of inflammatory cells, in particular lymphocytic reactions. The results yielded suggest some extent of anti-tumour immunity is present in colorectal cancers in humans.

Over the past 10 years there has been notable progress and an accumulation of scientific evidence for the concept of cancer immunosurveillance and immunoediting based on (i) protection against development of spontaneous and chemically-induced tumors in animal systems and (ii) identification of targets for immune recognition of human cancer.

Immunosurveillance

Cancer immunosurveillance is a theory formulated in 1957 by Burnet and Thomas, who proposed that lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...

s act as sentinels in recognizing and eliminating continuously arising, nascent transformed cells. Cancer immunosurveillance appears to be an important host protection process that inhibits carcinogenesis
Carcinogenesis
Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...

 and maintains regular cellular homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...

. It has also been suggested that immunosurveillance primarily functions as a component of a more general process of cancer immunoediting.

Immunoediting

Immunoediting is a process by which a person is protected from cancer growth and the development of tumour immunogenicity by their immune system. It has three main phases: elimination, equilibrium and escape. The elimination phase consists of the following four phases:

Elimination: Phase 1

The first phase of elimination involves the initiation of antitumor immune response. Cells of the innate immune system recognise the presence of a growing tumor which has undergone stromal remodeling, causing local tissue damage. This is followed by the induction of inflammatory signals which is essential for recruiting cells of the innate immune system (eg. natural killer cells, natural killer T cells, macrophages and dendritic cells) to the tumor site. During this phase, the infiltrating lymphocytes such as the natural killer cells and natural killer T cells are stimulated to produce IFN-gamma.

Elimination: Phase 2

In the second phase of elimination, newly synthesised IFN-gamma induces tumor death (to a limited amount) as well as promoting the production of chemokines CXCL10, CXCL9 and CXCL11. These chemokines play an important role in promoting tumor death by blocking the formation of new blood vessels. Tumor cell debris produced as a result of tumor death is then ingested by dendritic cells, followed by the migration of these dendritic cells to the draining lymph nodes. The recruitment of more immune cells also occurs and is mediated by the chemokines produced during the inflammatory process.

Elimination: Phase 3

In the third phase, natural killer cells and macrophages transactivate one another via the reciprocal production of IFN-gamma and IL-12. This again promotes more tumor killing by these cells via apoptosis and the production of reactive oxygen and nitrogen intermediates. In the draining lymph nodes, tumor-specific dendritic cells trigger the differentiation of Th1 cells which in turn facilitates the development of CD8+ T cells.

Elimination: Phase 4

In the final phase of elimination, tumor-specific CD4+ and CD8+ T cells home to the tumor site and the cytolytic T lymphocytes then destroy the antigen-bearing tumor cells which remain at the site.

Equilibrium and Escape

Tumor cell variants which have survived the elimination phase enter the equilibrium phase. In this phase, lymphocytes and IFN-gamma exert a selection pressure on tumor cells which are genetically unstable and rapidly mutating. Tumor cell variants which have acquired resistance to elimination then enter the escape phase. In this phase, tumor cells continue to grow and expand in an uncontrolled manner and may eventually lead to malignancies. In the study of cancer immunoeditting, knockout mice have been used for experimentation since human testing is not possible. Tumor infiltration by lymphocytes is seen as a reflection of a tumor-related immune response.

Cancer Immunology and 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.

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.

The role of viruses in cancer development

Various strains of Human Papilloma Virus (HPV) have recently been found to play an important role in the development of cervical cancer. The HPV oncogenes E6 and E7 that these viruses possess have been shown to immortalise some human cells and thus promote cancer development. Although these strains of HPV have not been found in all cervical cancers, they have been found to be the cause in roughly 70% of cases. The study of these viruses and their role in the development of various cancers is still continuing, however a vaccine has been developed that can prevent infection of certain HPV strains, and thus prevent those HPV strains from causing cervical cancer, and possibly other cancers as well.

A virus that has been shown to cause breast cancer in mice is Mouse Mammary Tumour Virus
Mouse mammary tumor virus
Mouse mammary tumor virus is a milk transmitted retrovirus like the HTL viruses, HI viruses and BLV. It belongs to the genus betaretroviruses. MMTV was formerly known as Bittner virus, and previously the 'milk factor' referring to the extra-chromosomal vertical transmission of murine breast cancer...

. It is from discoveries such as this and the role of HPV in cervical cancer development that research is currently being undertaken to discover whether or not Human Mammary Tumour Virus is a cause of breast cancer in humans.

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