Cancer Immunology

Immunology is a branch of biology that covers the study of immune systems in all organisms. It was the Russian biologist Ilya Ilyich Mechnikov who boosted studies on immunology, and received the Nobel Prize in 1908 for his work. He jabbed the thorn of a rose on a starfish and noted that, 24 hours later, cells were surrounding the tip. It was an active response of the body, trying to maintain its integrity. It was Mechnikov who first observed the phenomenon of phagocytosis, in which the body defends itself against a foreign body, and coined the term. Immunology charts, measures, and contextualizes the: physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders (such as autoimmune diseases, hypersensitivities, immune deficiency, and transplant rejection); the physical, chemical and physiological characteristics of the components of the immune system in vitro, in situ, and in vivo. Immunology has applications in numerous disciplines of medicine, particularly in the fields of organ transplantation, oncology, virology, bacteriology, parasitology, psychiatry, and dermatology.

Prior to the designation of immunity from the etymological root immunis, which is Latin for “exempt”; early physicians characterized organs that would later be proven as essential components of the immune system. The important lymphoid organs of the immune system are the thymus and bone marrow, and chief lymphatic tissues such as spleen, tonsils, lymph vessels, lymph nodes, adenoids, and liver. When health conditions worsen to emergency status, portions of immune system organs including the thymus, spleen, bone marrow, lymph nodes and other lymphatic tissues can be surgically excised for examination while patients are still alive.

Many components of the immune system are typically cellular in nature and not associated with any specific organ; but rather are embedded or circulating in various tissues located throughout the body
Cancer Immunology

Cancer immunology is a branch of immunology that studies interactions between the immune system and cancer cells (also called tumors or malignancies). It is a field of research that aims to discover cancer immunotherapies to treat and retard progression of the disease. The immune response, including the recognition of cancer-specific antigens, forms the basis of targeted therapy (such as vaccines and antibody therapies) and tumor marker-based diagnostic tests. For instance tumour infiltrating lymphocytes are significant in human colorectal cancer.[3] The host was given a better chance at survival if the cancer tissue showed infiltration of inflammatory cells, in particular those prompting lymphocytic reactions. The results yielded suggest some extent of anti-tumour immunity is present in colorectal cancers in humans.

Cancer immunosurveillance and immunoediting is 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.[4]

Immunosurveillance

Cancer immunosurveillance is a theory formulated in 1957 by Burnet and Thomas, who proposed that lymphocytes 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 and maintaining of regular cellular homeostasis.[6] 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.

Elimination

The elimination phase consists of the following four phases:

  • The first phase of elimination involves the initiation of an antitumor immune response. Cells of the innate immune system recognize 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 (e.g. 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.
  • In the second phase of elimination, newly synthesized 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.
  • 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 cytotoxic CD8+T cells also known as killer T-cells.
  • In the final phase of elimination, tumor-specific CD4+ and CD8+ T cells home to the tumor site and the cytotoxic 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 the escape phase, tumor cells continue to grow and expand in an uncontrolled manner and may eventually lead to malignancies. In the study of cancer immunoediting, knockout mice have been used for experimentation since human testing is not possible.[4] Tumor infiltration by lymphocytes is seen as a reflection of a tumor-related immune response.[8] There is increasing evidence that biological vesicles (eg, exosomes) secreted by tumour cells help to foster an immunosuppresive tumour microenvironment.[9]

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. 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.

The role of viruses in cancer development

  • Various strains of human papillomavirus (HPV) have 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 tumor virus. 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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