Immunoediting is a dynamic process that consists of

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 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''.

Definition

Immunoediting is characterized by changes in the

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 ...

of tumors due to the anti-tumor response of the immune system, resulting in the emergence of immune-resistant variants.

Phase 1: Elimination

The ''elimination phase'', also known as

, includes innate and adaptive immune responses to tumour cells. For the innate immune response, several effector cells such as

natural killer cell 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 repres ...

s and

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 are activated by the inflammatory

cytokines Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

, which are released by the growing tumour cells, macrophages and stromal cells surrounding the tumour cells. The recruited tumour-infiltrating NK cells and macrophages produce

interleukin 12 Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, and human B- lymphoblastoid cells ( NC-37) in response to antigenic stimulation. IL-12 belongs to the family of interleukin-12. I ...

and

interferon gamma 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 ...

, which kill tumour cells by cytotoxic mechanisms such as

perforin Perforin-1 is a protein that in humans is encoded by the ''PRF1'' gene and the ''Prf1'' gene in mice. Function Perforin is a pore forming cytolytic protein found in the granules of cytotoxic T lymphocytes (CTLs) and natural killer cells (NK ce ...

, TNF-related apoptosis-inducing ligands (

TRAIL A trail, also known as a path or track, is an unpaved lane or small road usually passing through a natural area. In the United Kingdom and the Republic of Ireland, a path or footpath is the preferred term for a pedestrian or hiking trail. Th ...

s), and

reactive oxygen species In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...

. Most of the tumor cells are destroyed in this phase, but some of them survive and are able to reach equilibrium with the immune system. The elimination phase consists of the following four phases: The first phase 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 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 ...

, natural killer T cells,

macrophages 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 ...

and

dendritic cells 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. The ...

) 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 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 ...

. In the second phase, newly synthesized IFN-gamma induces tumor death (to a limited amount) as well as promoting the production of

chemokines Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition ...

CXCL10 C-X-C motif chemokine ligand 10 (CXCL10) also known as Interferon gamma-induced protein 10 (IP-10) or small-inducible cytokine B10 is an 8.7 kDa protein that in humans is encoded by the ''CXCL10'' gene. C-X-C motif chemokine 10 is a small cytokin ...

, CXCL9 and

CXCL11 C-X-C motif chemokine 11 (CXCL11) is a protein that in humans is encoded by the ''CXCL11'' gene. C-X-C motif chemokine 11 is a small cytokine belonging to the CXC chemokine family that is also called ''Interferon-inducible T-cell alpha chemoattra ...

. 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 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 includ ...

. 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 In the context of gene regulation: transactivation is the increased rate of gene expression triggered either by biological processes or by artificial means, through the expression of an intermediate transactivator protein. In the context of rece ...

one another via the reciprocal production of IFN-gamma and IL-12. This again promotes more tumor killing by these cells via

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 ...

and the production of

reactive oxygen In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular 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, 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.

Phase 2: Equilibrium

The next step in cancer immunoediting is the ''equilibrium phase'', during which tumor cells that have escaped the ''elimination phase'' and have a non-immunogenic phenotype are selected for growth. Lymphocytes and

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. It is the longest of the three processes in cancer immunoediting and may occur over a period of many years. During this period of Darwinian selection, new tumor cell variants emerge with various mutations that further increase overall resistance to immune attack.

Phase 3: Escape

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. Tumor infiltration by lymphocytes is seen as a reflection of a tumor-related immune response. There is increasing evidence that biological vesicles (e.g., exosomes) secreted by tumour cells help to foster an immunosuppressive tumour microenvironment. During the ''escape phase'', tumor cell variants selected in the ''equilibrium phase'' have breached the host organism's immune defenses, with various genetic and

epigenetic In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...

changes conferring further resistance to immune detection. There are several mechanisms that lead to escape of cancer cells to immune system, for example downregulation or loss of expression of classical MHC class I (HLA-A, HLA-B- HLA-C) which is essential for effective T cell-mediated immune response (appears in up to 90% of tumours), development of cancer microenvironment which has suppressive effect on immune system and works as an protective barrier to cancer cells. Cells contained in tumor microenvironment are able to produce cytokines which can cause apoptosis of activated T lymphocyte. Another mechanism of tumor cells to avoid immune system is upregulation of non-classical MHC I (HLA-E, HLA-F, HLA-G) which prevents NK-mediated immune reaction by interaction with NK cells. The tumor begins to develop and grow after escaping the immune system.

Immunoediting in HIV

Recent studies suggest that cells harboring the HIV reservoir may also be undergoing a process of immunoediting, thereby contributing to the increased resistance of these cells to be eliminated by host immune factors.{{Cite journal, last1=Huang, first1=Szu-Han, last2=McCann, first2=Chase, last3=Mota, first3=Talia, last4=Wang, first4=Chao, last5=Lipkin, first5=Steven, last6=Jones, first6=R. Brad, date=2019-08-06, title=Have Cells Harboring the HIV Reservoir Been Immunoedited?, journal=Frontiers in Immunology, volume=10, pages=1842, issn=1664-3224, doi=10.3389/fimmu.2019.01842, pmid=31447850, pmc=6691121, doi-access=free

References