Cancer immunoediting integrating immunity s roles in cancer suppression and promotion
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Cancer Immunoediting Integrating Immunity ’ s Roles in Cancer Suppression and Promotion. Omer GULLULU. T he immune system plays a dual role in cancer : Destruction Provide a host region.

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Cancer Immunoediting Integrating Immunity ’ s Roles in Cancer Suppression and Promotion

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Cancer immunoediting integrating immunity s roles in cancer suppression and promotion

CancerImmunoeditingIntegratingImmunity’sRoles in CancerSuppressionandPromotion

Omer GULLULU


Cancer immunoediting integrating immunity s roles in cancer suppression and promotion

The immune systemplays a dual role in cancer:

  • Destruction

  • Provide a hostregion


Cancer immunoediting integrating immunity s roles in cancer suppression and promotion

BurnetandThomas built their cancerimmunosurveillance hypothesis,a concept that formally envisaged thatadaptiveimmunity was responsible for preventingcancer development in immunocompetenthosts.


Cancer immunoediting integrating immunity s roles in cancer suppression and promotion

Stutmanprovided little support for thishypothesis. Ofparticular note were experimentsshowing thatthe cancersusceptibility of immunocompetentmice(toboth spontaneous and carcinogen-inducedtumors)was similar to that of nude mice thathadmajor but not total immunodeficiency


Cancer immunoediting integrating immunity s roles in cancer suppression and promotion

Three views;

  • Tumor cells did not possess the appropriate “danger signals” needed to alert the immune system to the presence of a foreign cell.

  • The immune system would ignore or be tolerant to a developing tumor because tumor cells were too similar to the normal cells from which they were derived.

  • Pro-inflammatory arm of immunity could facilitate cellular transformation and promote cancer outgrowth and argued that this effect of immunity precluded its capacity to fulfill a protective function.


Effects of inf and stat1

Effects of INF-γand STAT1

The discovery of the importance ofinterferon-gamma(IFN-γ) in promoting immunologicallyinduced rejection of transplanted tumorcells and by the demonstration that mice lackingeither IFN-γresponsiveness (gene-targetedmice lacking either the IFN-γreceptor or theSTAT1 transcription factor required for IFN receptorsignaling) or adaptive immunity [RAG2−/−mice lackingT cells, B cells, and natural killerT (NKT)cells]weremore susceptible tocarcinogeninducedand spontaneous primary tumor formation.


Distinct roles of immune system

DistinctRoles of ImmuneSystem

  • It protects the host against viral infection

  • It prevents thetumorigenesis

  • It eliminatestumor cells in certain tissues


Tumor antigens and cancer immunosurveillance

Tumor Antigens and Cancer Immunosurveillance

Cancercellsexpressantigens ?


Cancer immunoediting integrating immunity s roles in cancer suppression and promotion

In the case of human cancer, identification oftumor antigens required the development ofnovel in vitro detection and cloning methodsthat used as probes antibodies and cytolyticTlymphocytes (CD8 T cells) derived fromcancer patients that were specific for theautologous tumor.


Antigen presentation stimulates t cells to become either cytotoxic cd8 cells or helper cd4 cells

Antigen presentation stimulates T cells to become either "cytotoxic" CD8+ cells or "helper" CD4+ cells.


Cancer immunoediting integrating immunity s roles in cancer suppression and promotion

  • Thehumantumorantigens;

  • Differentiationantigens (such as melanocytedifferentiationantigens)

  • Mutationalantigens (such as p53)

  • Overexpressedcellularantigens (such as HER-2 (Human Epidermal Growth Factor Receptor 2))

  • Viralantigens (such as humanpapillomavirusproteins)

  • Cancer/testis (CT) antigens


The c ancer i mmunoediting h ypothesis

TheCancerImmunoeditingHypothesis

Notonly tumor quantity but also tumor quality


Cancer immunoediting integrating immunity s roles in cancer suppression and promotion

The notion that the immune system not only protects the host against tumor formation but also shapes tumor immunogenicity is the basis of the cancer immunoediting hypothesis, which stresses the dual host-protective and tumor-promoting actions of immunity on developing tumors.


Cancer immunoediting integrating immunity s roles in cancer suppression and promotion

  • Thecancerimmunoeditingprocessproceedsthroughthreedistinctphases:

  • Elimination

  • Equilibrium

  • Escape


Cancer immunoediting integrating immunity s roles in cancer suppression and promotion

Immunosuppressivecytokines;

  • Vascularendothelialgrowthfactor (VEGF)

  • Transforminggrowthfactor–β (TGF-β)

  • Galectin

  • Indoleamine2,3-dioxygenase (IDO)


Cancer immunoediting integrating immunity s roles in cancer suppression and promotion

Regulatory T cells (Treg cells) and myeloid-derived suppressor cells (MDSCs) are two major types of immunosuppressive leukocyte populations that play key roles in inhibiting host-protective antitumor responses.


Cancer immunoediting integrating immunity s roles in cancer suppression and promotion

Thenegativeco-stimulatorycytokines;

  • CTLA-4 (Cytotoxic T-LymphocyteAntigen4)

  • Programmed cell death protein 1 (PD-1)

    • PD-L1

    • PD-L2

  • Interleukin 2 (IL-2)


Cancer immunoediting versus inflammation

CancerImmunoeditingVersusInflammation

Inducingcellularproliferation

Genotoxicstress – (Cancerpromotion)

EnhancingangiogenesisTissueinvasion

Cancerprogression

ChronicinflammationTumorigenesis


P ro inflammatory cytokines signaling

Pro-inflammatorycytokines/signaling

Control components of immunity

  • IL-1β

  • IL-23

  • MyD88

  • IFN-γ

  • IFN-α/β

  • IL-12

  • T cells

Interaction


Cancer immunoediting integrating immunity s roles in cancer suppression and promotion

MyD88 and IL-1β

  • Promotecarcinogen-induced tumorigenesis ?

  • Promotedevelopment of protective immune responses against established tumors by facilitating recognition of tumor cells undergoing “immunogenic death” ?


Tumor necrosis factor alpha tnf

TumorNecrosisFactor-Alpha ( TNF-α)

Regulators of G-Protein Signaling (RGS)

IntraOcularPressure-InducedIschemia (IOP Ischemia)


Cancer immunoediting in humans

CancerImmunoediting in Humans

  • Intratumoral immune responsespredictpatientprognosis

CD4+ T cells

PromoteTumor Control

IFN-γ

CD8+ T cells

TNF-α


Cancer immunoediting integrating immunity s roles in cancer suppression and promotion

  • Spontaneousimmuneresponses in cancerpatients

  • Paraneoplasticneurologicdisorders (PNDs). PNDsarise as a consequence of antibody and T cellresponsesagainstcertainautologoustumorsthatectopically express proteins normally expressedonly in cells of the nervous system.


Cancer immunoediting integrating immunity s roles in cancer suppression and promotion

  • Immunodeficiency is associated with a higher risk of cancer

  • Immunodeficiency has beenlinkedto increased cancer risk in patients with AIDSandin transplant recipients maintained onimmunosuppressants.

  • Insights into the role of the immune system inhumancancer have also come from anecdotalreports ofcancer being transferred from an organdonor to the immunosuppressed recipient.


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