Immunoediting

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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. [1]

Contents

Definition

Immunoediting is characterized by changes in the immunogenicity of tumors due to the anti-tumor response of the immune system, resulting in the emergence of immune-resistant variants. [2]

Phase 1: Elimination

During the elimination phase, immune effector cells such as natural killer cells, with the help of dendritic and CD4+ T-cells, are able to recognize and eliminate tumor cells (left). As a result of heterogeneity, however, tumor cells which are less immunogenic are able to escape immunosurveillance (right). Tumor microenvironment.jpg
During the elimination phase, immune effector cells such as natural killer cells, with the help of dendritic and CD4+ T-cells, are able to recognize and eliminate tumor cells (left). As a result of heterogeneity, however, tumor cells which are less immunogenic are able to escape immunosurveillance (right).

The elimination phase, also known as immunosurveillance, includes innate and adaptive immune responses to tumour cells. For the innate immune response, several effector cells such as natural killer cells and T cells are activated by the inflammatory cytokines, 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 and interferon gamma, which kill tumour cells by cytotoxic mechanisms such as perforin, TNF-related apoptosis-inducing ligands (TRAILs), and reactive oxygen species. [3] [1] [4] 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 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, 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, 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 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. 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. [3]

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. [5] There is increasing evidence that biological vesicles (e.g., exosomes) secreted by tumour cells help to foster an immunosuppressive tumour microenvironment. [6] 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 changes conferring further resistance to immune detection. [1] 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) [7] [4] which is essential for effective T cell-mediated immune response (appears in up to 90% of tumours [7] ), development of cancer microenvironment which has suppressive effect on immune system [8] 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. [9] 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. [10] [11] [4] 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. [12]

See also

Related Research Articles

Natural killer cell Type of cytotoxic lymphocyte

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 innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cell and other intracellular pathogens acting at around 3 days after infection, and respond to tumor formation. Typically, immune cells detect the major histocompatibility complex (MHC) presented on infected cell surfaces, triggering cytokine release, causing the death of the infected cell by lysis or apoptosis. NK cells are unique, however, as they have the ability to recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class 1. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

Cell-mediated immunity is an immune response that does not involve antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.

Cancer immunotherapy Artificial stimulation of the immune system to treat cancer

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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. IL-12 family is unique in comprising the only heterodimeric cytokines, which includes IL-12, IL-23, IL-27 and IL-35. Despite sharing many structural features and molecular partners, they mediate surprisingly diverse functional effects.

Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucosa (endometrium), prostate, bone marrow, lymph node and the ovary. They are cells that support the function of the parenchymal cells of that organ. The most common stromal cells include fibroblasts and pericytes. The term stromal comes from Latin stromat-, "bed covering", and Ancient Greek στρῶμα, strôma, "bed".

Interferon gamma

Interferon gamma (IFNγ) 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 as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes. It was also shown to be produced in human lymphocytes. or tuberculin-sensitized mouse peritoneal lymphocytes challenged with Mantoux test (PPD); the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed interferon gamma release assay used to test for tuberculosis. In humans, the IFNγ protein is encoded by the IFNG gene.

CXCL9

Chemokine ligand 9 (CXCL9) is a small cytokine belonging to the CXC chemokine family that is also known as monokine induced by gamma interferon (MIG). The CXCL9 is one of the chemokine which plays role to induce chemotaxis, promote differentiation and multiplication of leukocytes, and cause tissue extravasation.

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 cytokine belonging to the CXC chemokine family.

Interferon type II

A sole member makes up the type II interferons (IFNs) that is called IFN-γ (gamma). Mature IFN-γ is an anti-parallel homodimer, which binds to the IFN-γ receptor (IFNGR) complex to elicit a signal within its target cell. IFNGR is made up of two subunits each of molecules designated IFNGR1 and IFNGR2.

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Cancer immunology

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Tumor microenvironment

The tumor microenvironment (TME) is the environment around a tumor, including the surrounding blood vessels, immune cells, fibroblasts, signaling molecules and the extracellular matrix (ECM). The tumor and the surrounding microenvironment are closely related and interact constantly. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.

Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the peripheral blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the absence of regular lymphoid morphology, rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immune cells from the myeloid lineage.

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References

  1. 1 2 3 Dunn, Gavin P.; Old, Lloyd J.; Schreiber, Robert D. (2004). "The Three Es of Cancer Immunoediting". Annual Review of Immunology. 22 (1): 329–360. CiteSeerX   10.1.1.459.1918 . doi:10.1146/annurev.immunol.22.012703.104803. PMID   15032581.
  2. ↑ "Immunoediting". Springer Science+Business Media . Retrieved 26 June 2014.
  3. 1 2 Kim, Ryungsa; Emi, Manabu; Tanabe, Kazuaki (2007). "Cancer immunoediting from immune surveillance to immune escape". Immunology. 121 (1): 1–14. doi:10.1111/j.1365-2567.2007.02587.x. PMC   2265921 . PMID   17386080.
  4. 1 2 3 Wagner, Marek; Koyasu, Shigeo (May 2019). "Cancer Immunoediting by Innate Lymphoid Cells". Trends in Immunology. 40 (5): 415–430. doi:10.1016/j.it.2019.03.004. PMID   30992189. S2CID   119093972.
  5. ↑ Odunsi K, Old LJ (2007). "Tumor infiltrating lymphocytes: indicators of tumor-related immune responses". Cancer Immunity. 7: 3. PMC   2935754 . PMID   17311362.
  6. ↑ Syn, Nicholas; Wang, Lingzhi; Sethi, Gautam; Thiery, Jean-Paul; Goh, Boon-Cher (2016-07-01). "Exosome-Mediated Metastasis: From Epithelial-Mesenchymal Transition to Escape from Immunosurveillance". Trends in Pharmacological Sciences. 37 (7): 606–617. doi:10.1016/j.tips.2016.04.006. ISSN   1873-3735. PMID   27157716.
  7. 1 2 Garrido, Federico; Romero, Irene; Aptsiauri, Natalia; Garcia-Lora, Angel M. (2016-01-15). "Generation of MHC class I diversity in primary tumors and selection of the malignant phenotype". International Journal of Cancer. 138 (2): 271–280. doi: 10.1002/ijc.29375 . ISSN   1097-0215. PMID   25471439.
  8. ↑ Balkwill, Frances R.; Capasso, Melania; Hagemann, Thorsten (2012-12-01). "The tumor microenvironment at a glance". Journal of Cell Science. 125 (Pt 23): 5591–5596. doi: 10.1242/jcs.116392 . ISSN   1477-9137. PMID   23420197.
  9. ↑ Dong, Haidong; Strome, Scott E.; Salomao, Diva R.; Tamura, Hideto; Hirano, Fumiya; Flies, Dallas B.; Roche, Patrick C.; Lu, Jun; Zhu, Gefeng (2002). "Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion". Nature Medicine. 8 (8): 793–800. doi:10.1038/nm730. PMID   12091876. S2CID   27694471.
  10. ↑ Borrego, F.; Ulbrecht, M.; Weiss, E. H.; Coligan, J. E.; Brooks, A. G. (1998-03-02). "Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis". The Journal of Experimental Medicine. 187 (5): 813–818. doi:10.1084/jem.187.5.813. ISSN   0022-1007. PMC   2212178 . PMID   9480992.
  11. ↑ Paul, P.; Rouas-Freiss, N.; Khalil-Daher, I.; Moreau, P.; Riteau, B.; Le Gal, F. A.; Avril, M. F.; Dausset, J.; Guillet, J. G. (1998-04-14). "HLA-G expression in melanoma: a way for tumor cells to escape from immunosurveillance". Proceedings of the National Academy of Sciences of the United States of America. 95 (8): 4510–4515. Bibcode:1998PNAS...95.4510P. doi: 10.1073/pnas.95.8.4510 . ISSN   0027-8424. PMC   22520 . PMID   9539768.
  12. ↑ Huang, Szu-Han; McCann, Chase; Mota, Talia; Wang, Chao; Lipkin, Steven; Jones, R. Brad (2019-08-06). "Have Cells Harboring the HIV Reservoir Been Immunoedited?". Frontiers in Immunology. 10: 1842. doi: 10.3389/fimmu.2019.01842 . ISSN   1664-3224. PMC   6691121 . PMID   31447850.
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