Tumor Immunology

Learning contents -Etiology of cancer. -Tumor immunology introduction. -Tumor Antigens. - Immune Response to tumors. -Tumor escape mechanisms.

Cancer Etiology -The proliferation of normal cells is carefully regulated. -However, such cells when exposed to different carcinogens may undergo mutations leading to their transformation into cells that are capable of uncontrolled growth, producing a tumor or neoplasm. 

Types of tumors A tumor may be: 1- Benign, if it is not capable of indefinite growth and the host survives. 2- Malignant, if the tumor continues to grow indefinitely and spreads (metastasizes), eventually killing the host.

Cancer Etiology The uncontrolled growth may be due to: - Upregulation of proto-oncogenes into oncogenes (cancer-inducing genes). - Downregulation of tumor suppressor genes (that normally inhibit tumor growth often by inducing cell death).

Cancer Etiology And that maybe induced by: -Inherited: Expression of inherited oncogene e.g. viral gene incorporated into host gene -Viral: Human papilloma, herpes type 2, HBV, -Chemical: - Poly cyclic hydrocarbons and aromatic amines -Radiological: Ultraviolet & ionizing irradiation -Spontaneous: failure in the cellular growth control.

Cancer and immune system -The idea that the immune system, which so effectively protects the host from microbial pathogens, might also recognize and destroy tumor cells was first discussed over a century ago and has recently been reviewed in detail .

Cancer and immune system The immune system has three primary roles in the prevention of tumors: 1- by protecting the host from virus-induced tumors by eliminating or suppressing viral infections. 2- by the elimination of pathogens and prompt resolution of inflammation can prevent the establishment of an inflammatory environment conducive to tumorigenesis. 3- and specifically by identifying and eliminating tumor cells on the basis of their expression of tumor-specific antigens or molecules induced by cellular stress. *The third process is referred to as tumor immune surveillance, whereby the immune system identifies cancerous and/or precancerous cells and eliminates them before they can cause harm.

Cancer and immune system -The tumor immunoediting concept is divided into 3 phases, designated elimination, equilibrium, and escape . -The elimination phase of cancer immunoediting is exactly the same process described in the initial theory of tumor immune surveillance, whereby the immune system detects and eliminates tumor cells that have developed as a result of failed intrinsic tumor suppressor mechanisms. -The elimination phase can be complete, when all tumor cells are cleared, or incomplete, when only a portion of tumor cells are eliminated. In the case of partial tumor elimination, the theory of immunoediting is that a temporary state of equilibrium can then develop between the immune system and the developing tumor.

Cancer and immune system -During this period it is envisaged that tumor cells either remain dormant or continue to evolve, accumulating further changes (such as DNA mutations or changes in gene expression) that can modulate the tumor-specific antigens and stress-induced antigens that they express. -As this process continues, the immune system exerts a selective pressure by eliminating susceptible tumor clones where possible.

Cancer and immune system -The pressure exerted by the immune system during this phase is sufficient to control tumor progression, but eventually, if the immune response still fails to completely eliminate the tumor, the process results in the selection of tumor cell variants that are able to resist, avoid, or suppress the antitumor immune response, leading to the escape phase. -During the escape phase the immune system is no longer able to contain tumor growth, and a progressively growing tumor results.

Evidence for existence of an immune response against tumors: 1. Certain tumors regress spontaneously (e.g., melanomas).suggesting an immunological response. 2. Tumors that have severe mononuclear cell infiltration have a better prognosis than those that lack it. 3. Some tumor metastases regress after removal of primary tumor which reduces the tumor load, thereby inducing the immune system to kill the residual tumor.   4. Higher incidence of cancer after immunosuppression, immunodeficiency (AIDS, neonates).

Evidence for existence of an immune response against tumors: 5. Tumor-specific antibodies and T lymphocytes (detected in cytotoxicity and proliferative response assays) have been observed in patients with tumors. 6. The young and the old population have an increased incidence of tumors. These members of the population often have an immune system that is compromised. 7. Hosts can be specifically immunized against various types of tumors demonstrating tumor Ags can elicit an immune response.

Tumor antigens Tumorigenesis may lead to expression of new antigens or alteration in existing antigens that are found on normal cells.

Tumor antigens There are 2 main types of tumor antigens:   Tumor-specific transplantation antigens (TSTA) which are unique to tumor cells and not expressed on normal cells. They are responsible for rejection of the tumor. Tumor associated transplantation antigens (TATA) that are expressed by tumor cells and normal cells.

Tumor antigens

Tumor- specific transplantation antigens (TSTA) -Although chemical- , UV- or virus-induced tumors express neo-antigens, majority of the tumors are often weakly immunogenic or non-immunogenic. - In most cases, tumor-specific transplantation Ags cannot be identified easily. Also, some of these antigens may be secreted while others include membrane-associated molecules.  

Tumor- specific transplantation antigens..cont Chemically-induced tumors: They are different from virally-induced tumors in that they are extremely heterogeneous in their antigenic characteristics. Thus, any two tumors induced by the same chemical, even in the same animal, rarely share common tumor specific antigens. These unique antigens on chemically-induced tumors are referred to as tumor-specific transplantation antigens (TSTA).

Tumor associated transplantation antigens (TATA) -The majority of tumor Ags are the tumor associated transplantation antigens. -They may be expressed at higher levels on tumor cells when compared to normal cells. Alternatively, they may be expressed only during development of cells and lost during adult life but re-expressed in tumors. These include the: 1-tumor-associated developmental Ags (TADA) 2-tumor-associated viral Ags (TAVA).

Tumor associated transplantation antigens (TATA) 1- Tumor-associated developmental Ags (TADA) or Onco-fetal antigens. These include: - alpha-fetoprotein (AFP)--- in hepatocellular carcinoma. carcinoma. -carcino-embryonic antigen (CEA) ---- in colon cancer. *These are important in diagnosis.

Tumor associated transplantation antigens (TATA) 2-tumor-associated viral Ags (TAVA). Viruses that cause tumors include: DNA viruses: 1. Papova (papilloma, polyoma) viruses. Ex. Papilloma virus causes cervical cancer. 2. Hepatitis virus: Hepatitis B virus causes hepatocellular cancer. 3. Adenoviruses    RNA viruses: Retroviruses: Human T-lymphotropic viruses (HTLV-I and HTLV-II) causes adult T cell leukemia. Virus-induced tumors express tumor-associated viral Ags (TAVA). These are cell surface antigens that are distinct from antigens on the virion itself. However, these transplantation-associated viral Ags are shared by all tumors induced by the same virus, regardless of tissue origin of the tumor or animal in which the tumor exists

Immune Response to tumors Cellular Cytotoxic T lymphocytes. Natural killer cells. Macrophages. Humeral mechanisms ADCC (Antibody dependent cellular cytotoxicity)

Immune Response to tumors

Immune Response to tumors While Abs may develop against few cancers, cell-mediated immunity plays a critical role in tumor rejection. The T helper (Th) cells recognize the tumor Ags that may be shed from tumors and internalized, processed and presented in association with class II MHC on antigen presenting cells.

Immune Response to tumors These Th cells when activated will produce cytokines. Thus, the Th cells provide help to B cells in Ab production. The cytokines such as IFN-γ may also activate macrophages to become tumoricidal. Furthermore, the Th cells also provide help to tumor-specific cytotoxic T cells (CTL) by inducing their proliferation and differentiation.   The CTL recognize tumor Ags in the context of class I MHC and mediate tumor cell lysis.

Immune Response to tumors Recognition of tumor antigens by CTL is the result of a complex process, In this system an antigen is processed inside the target or antigen presenting cell (APC) into small peptide fragments that are then presented at the cell surface within the groove of the Major Histocompatibility Complex (MHC, HLA in humans) class 1 molecules. This complex is then recognized by a T cell receptor (TCR) presented on CTL. This TCR must be fitting to both the HLA allele present on the cell, and to the peptide presented.

Immune Response to tumors Though underestimated during the last few years, MHC Class II restricted recognition is also very important for the induction of antitumor CTL which are activated through a (CD4 mediated) T helper response. The outcome of antigen recognition though, is not necessarily tumor cell killing. Inflammation or destruction, occurring during infection, come with cytokine-mediated signals (e.g. TNF-a and GM-CSF), resulting in activation of T-lymphocytes.

Immune Response to tumors

Immune Response to tumors

Antigen presenting cells (APC) APC like macrophages, monocytes, B-cells and dendritic cells (DC). Presentation of antigen to naive T-lymphocytes without co-stimulation may lead to T cell tolerance. In fact, the adequate antigen presentation to a naive immune system occurs through these APC. With the possible exception of B-cell lymphoma, tumour cells seldom express costimulatory molecules.

Antigen presenting cells (APC) The most potent in terms of anti-tumour CTL induction is the APC subset known as dendritic cells (DC). To activate this process of antigen presentation by the DC, the antigen has to be present, along with signals of tissue damage, the so-called danger signals. Apart from their role in presentation of antigen to CTL, DC are also of importance in the induction of CD4 (T helper) and natural killer cell responses. This makes DC a central pivot of anti-tumour response, and implies great promises for clinical application.

Antibodies: Antibody dependent cellular cytotoxixity (ADCC) is an important tool in the eradication of intracellular pathogens and tumor cells. In such a case the antigens are expressed on the cell surface, usually in the form of transmembrane protein, and recognized by the antigen specific part of the antibodies. The tail of the antibody then binds to the Fc receptor on cells like NK cells and macrophages, resulting in signal of activation that can cause the lysis of target cells.

Tumor escape: According to the Immune Surveillance Theory, cancer cells that arise in the body are eliminated by the immune system. However, due to impaired immune reactivity, the cancer cells escape destruction.   These mechanisms can broadly be divided into those that are intrinsic to the tumor cells and those that are mediated by other cells.

Mechanisms of tumor cells to evade the immune system There are several mechanisms by which tumor cells appear to evade the immune system Down-regulation of class I MHC No express costimulators or class II molecules Lose expression of tumor antigens that elicit immune response Induce specific immunologic tolerance Suppress anti-tumor immune response Antigen masking: the cell surface antigens of tumors may be hidden from the immune system by glycocalyx molecules.

Intrinsic Mechanisms of Immune Evasion by Tumor Cells Several properties of tumor cells enable them to escape host defenses.

Intrinsic Mechanisms of Immune Evasion by Tumor Cells..Cont. Tumors may lose expression of antigens that elicit immune responses: Such “antigen loss variants” are common in rapidly growing tumors and can readily be induced in tumor cell lines by culture with tumor-specific antibodies or CTLs. Given the high mitotic rate of tumor cells and their genetic instability, mutations or deletions in genes encoding tumor antigens are common.

Intrinsic Mechanisms of Immune Evasion by Tumor Cells..Cont. Apart from tumor-specific antigens, class I MHC expression may be downregulated on tumor cells so that they cannot be recognized by CTLs. Various tumors show decreased synthesis of class I MHC molecules, β2-microglobulin, or components of the antigen-processing machinery.

Intrinsic Mechanisms of Immune Evasion by Tumor Cells..Cont. Tumor antigens may be inaccessible to the immune system cell surface antigens of tumors may be hidden from the immune system by glycocalyx molecules, such as sialic acid–containing mucopolysaccharides. This process is called antigen masking and may be a consequence of the fact that tumor cells often express more of these glycocalyx molecules than normal cells do.

Intrinsic Mechanisms of Immune Evasion by Tumor Cells..Cont. Tumors may fail to induce strong effector T cell responses because most tumor cells do not express costimulators or class II MHC molecules. Costimulators are required for initiation of T cell responses, and class II molecules are needed for the activation of helper T cells, which in some circumstances are required for the differentiation of CTLs. Therefore, the induction of tumor-specific T cell responses often requires cross-priming by dendritic cells, which do express costimulators and class II molecules.

Cont.. If such APCs do not adequately take up and present tumor antigens and activate helper T cells, CTLs specific for the tumor cells may not develop.

Intrinsic Mechanisms of Immune Evasion by Tumor Cells...Cont. Tumors may engage molecules that inhibit immune responses. There is good experimental evidence that T cell responses to some tumors are inhibited by the involvement of CTLA-4 or PD-1, two of the best-defined inhibitory pathways in T cells. A possible reason for this role of CTLA-4 is that tumor antigens are presented by APCs in the absence of strong innate immunity and thus with low levels of B7 costimulators.

Cont.. PD-L1 on APCs may also be involved in inhibiting tumor-specific T cell activation. Some tumors express Fas ligand (FasL), which recognizes the death receptor Fas on leukocytes that attempt to attack the tumor; engagement of Fas by FasL may result in apoptotic death of the leukocytes.

Intrinsic Mechanisms of Immune Evasion by Tumor Cells..Cont. Secreted products of tumor cells may suppress anti-tumor immune responses. An example of an immunosuppressive tumor product is TGF-β, which is secreted in large quantities by many tumors and inhibits the proliferation and effector functions of lymphocytes and macrophages.

Extrinsic Cellular Suppression of Anti-Tumor Immunity Several cell populations have been described in tumor-bearing patients and animals that suppress anti-tumor immunity.

Extrinsic Cellular Suppression of Anti-Tumor Immunity Tumor-associated macrophages may promote tumor growth and invasiveness by altering the tissue microenvironment and by suppressing T cell responses. These macrophages have an M2 phenotype, and they secrete mediators, such as IL-10, prostaglandin E2, and arginase, that impair T cell activation and effector functions. Tumor-associated macrophages also secrete factors that promote angiogenesis, such as TGF-β and VEGF, which enhances tumor growth.

Extrinsic Cellular Suppression of Anti-Tumor Immunity Regulatory T cells may suppress T cell responses to tumors. Evidence indicates that the numbers of regulatory T cells are increased in tumor-bearing individuals, and these cells can be found in the cellular infiltrates in certain tumors. Depletion of regulatory T cells in tumor-bearing mice enhances anti-tumor immunity and reduces tumor growth.

Extrinsic Cellular Suppression of Anti-Tumor Immunity Myeloid-derived suppressor cells (MDSCs) are immature myeloid precursors that are recruited from the bone marrow and accumulate in lymphoid tissues, blood, or tumors of tumor-bearing animals, cancer patients and suppress anti-tumor innate and T cell responses. MDSCs are a heterogeneous group of cell types, including precursors of dendritic cells, monocytes, and neutrophils. They share some common surface markers, CD33, CD11b, and CD15 in humans.

Extrinsic Cellular Suppression of Anti-Tumor Immunity Cont.. MDSCs suppress innate immune responses by secreting IL-10, which inhibits various macrophage inflammatory functions. MDSCs suppress T cell responses by a variety of mechanisms. They express arginase and inducible nitric oxide synthase, which work together in generating reactive oxygen species, such as peroxynitrite, that inhibit T cell activation.

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