Cancer Immunoediting

Integrating Immunity’s Roles in Cancer Suppression and

Promotion

Omer GULLULU

The immune system plays a dual role in cancer:

1. Destruction2. Provide a host region

Burnet and Thomas built their cancer immunosurveillance hypothesis, a concept that formally envisaged that adaptive immunity was responsible for preventing cancer development in immunocompetent hosts.

Stutman provided little support for this hypothesis. Of particular note were experiments showing that the cancer susceptibility of immunocompetent mice (to both spontaneous and carcinogen-induced tumors) was similar to that of nude mice that had major but not total immunodeficiency

Three views;

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

2. 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.

3. 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-γ and STAT1

The discovery of the importance of interferon-gamma (IFN-γ) in promoting immunologically induced rejection of transplanted tumor cells and by the demonstration that mice lacking either IFN-γ responsiveness (gene-targeted mice lacking either the IFN-γ receptor or the STAT1 transcription factor required for IFN receptor signaling) or adaptive immunity [RAG2−/− mice lacking T cells, B cells, and natural killer T (NKT) cells] were more susceptible to carcinogeninduced and spontaneous primary tumor formation.

Distinct Roles of Immune System

1. It protects the host against viral infection

2. It prevents the tumorigenesis

3. It eliminates tumor cells in certain tissues

Tumor Antigens and Cancer Immunosurveillance

Cancer cells express antigens ?

In the case of human cancer, identification of tumor antigens required the development of novel in vitro detection and cloning methods that used as probes antibodies and cytolytic T lymphocytes (CD8 T cells) derived from cancer patients that were specific for the autologous tumor.

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

The human tumor antigens;

1. Differentiation antigens (such as melanocyte differentiation antigens)

2. Mutational antigens (such as p53)3. Overexpressed cellular antigens (such as HER-2

(Human Epidermal Growth Factor Receptor 2))4. Viral antigens (such as human papillomavirus

proteins)5. Cancer/testis (CT) antigens

The Cancer Immunoediting Hypothesis

Not only tumor quantity but also tumor quality

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.

The cancer immunoediting process proceeds through three distinct phases:

1. Elimination2. Equilibrium3. Escape

Immunosuppressive cytokines;

1. Vascular endothelial growth factor (VEGF)2. Transforming growth factor–β (TGF-β)3. Galectin4. Indoleamine 2,3-dioxygenase (IDO)

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.

The negative co-stimulatory cytokines;

1. CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4)2. Programmed cell death protein 1 (PD-1)• PD-L1• PD-L2

3. Interleukin 2 (IL-2)

Cancer Immunoediting Versus Inflammation

Inducing cellular proliferation

Genotoxic stress – (Cancer promotion)

Enhancing angiogenesis Tissue invasion

Cancer progression

Chronic inflammation Tumorigenesis

Pro-inflammatory cytokines/signaling

• IL-1β• IL-23• MyD88

• IFN-γ• IFN-α/β• IL-12• T cells

Control components of immunity

Interaction

MyD88 and IL-1β

• Promote carcinogen-induced tumorigenesis ?

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

Tumor Necrosis Factor-Alpha ( TNF-α)

Regulators of G-Protein Signaling (RGS)IntraOcular Pressure-Induced Ischemia (IOP Ischemia)

Cancer Immunoediting in Humans

Intratumoral immune responses predict patient prognosis

CD4+ T cells

CD8+ T cells

IFN-γ

TNF-α

Promote Tumor Control

Spontaneous immune responses in cancer patients

• Paraneoplastic neurologic disorders (PNDs). PNDs arise as a consequence of antibody and T cell responses against certain autologous tumors that ectopically express proteins normally expressed only in cells of the nervous system.

Immunodeficiency is associated with a higher risk of cancer

• Immunodeficiency has been linked to increased cancer risk in patients with AIDS and in transplant recipients maintained on immunosuppressants.

• Insights into the role of the immune system in human cancer have also come from anecdotal reports of cancer being transferred from an organ donor to the immunosuppressed recipient.

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