Tumor immunity

TUMOR IMMUNITY

Presented by : Shoaib Irfan

IMMUNITY

ADAPTIVEINNATE

1. Cell- mediated immunity2. Humoral immunity (antibodies)

Immune cells

Lymphocytes

Small lymphocytes

T cells

Helper T cells Cytotoxic T cells

B cells

Large lymphocytes

NK cells

Antigen Presenting

cells

1. Dendritic cells2. B cells3. Macrophages

IMMUNOLOGY OF TUMOR

CLASSIFICATION OF TUMOR ANTIGENS•Tu

mor Specfic Antigens :EBV HPV HBV

•Tumor Associated Antigens : PSA CD10

A. BASED ON THEIR PATTERNS OF EXPRESSION

B. BASED ON THEIR MOLECULAR STRUCTURE AND SOURCE

1. Products of Mutated Oncogenes and Tumor Suppressor Genes

2. Over expressed or Aberrantly Expressed Cellular Proteins

3. Tumor Antigens Produced by Oncogenic Viruses

4. Oncofetal antigens

5. Altered glycolipids and glycoproteins

6. Cell type-specific differentiation antigens

CLASSIFICATION OF TUMOR ANTIGENS

TUMOR ANTIGENS

Products of mutated genes• Derived from the products of mutant proto-oncogenes,

tumor suppressor genes, or other mutated genes • Synthesized in the cytoplasm of tumor cells, and like any

cytoplasmic protein, they may enter the class I MHC antigenprocessing pathway and be recognized by CD8+ T cells

• These proteins may enter the class II antigen-processing pathway in antigen-presenting cells that have phagocytosed dead tumor cells, and thus be recognized by CD4+ T cells

TUMOR ANTIGENS

Products of mutated genes• Products of β-catenin, p53, RAS, and CDK4

BCR-ABL • Because the mutant proteins are present only in

tumors, their peptides are expressed only in tumor cells

TUMOR ANTIGENS

Oncofetal antigens• Proteins that are expressed at high levels on

tumor cells and in normal developing fetal cells but not adult tissues

• Their main importance is that they provide markers that aid in tumor diagnosis

TUMOR ANTIGENS

Oncofetal antigens• Carcino-embryonic antigens (CEA)• Normally expressed during fetal life on fetal gut• Colon Carcinoma

• Alpha fetoprotein(AFP):• Normally expressed in fetal life • Hepatocellular Carcinoma

TUMOR ANTIGENS

Antigens produced by oncogenic viruses• Oncogenic viruses produce proteins that are

recognized as foreign antigen by the immune system • EBV• HPV• HBV

TUMOR ANTIGENS

Altered Cell Surface Glycolipids and Glycoproteins

• Expression is higher than normal levels and abnormal forms of surface glycoproteins and glycolipids

• Diagnostic markers and targets for therapy

TUMOR ANTIGENS

Altered Cell Surface Glycolipids and Glycoproteins

• These include

• CA-125 - Ovarian carcinomas

• CA-19-9- Biliary & Pancreatic carcinoma

• MUC-1 - Breast carcinomas

TUMOR ANTIGENS

Cell Type-Specific Differentiation Antigens• typically normal self-antigens, and therefore

they do not induce immune responses in tumor-bearing hosts

• For example, lymphomas may be diagnosed as B-cell-derived tumors by the detection of surface markers characteristic of this lineage, such as CD10 and CD20

Immune Response to Tumors

Cellular Immunity

• CTL (Cytotoxic T-lymphoctyes)

• NK cells

• Macrophages

Humoral Immunity

• Antibody production by the host against host tumor cells or their constituents for tumor antigens

Immune Response to Tumors

CTL (Cytotoxic T-lymphoctyes)• CTLs are the major immune defense mechanism against

tumors • CTLs recognize peptides molecules which is derived from

cytoplasmic proteins that are displayed bound to class I major histocompatibility complex (MHC) molecules

• CTLs play a protective role against virus-associated neoplasms (e.g., EBV- and HPV-induced tumors)

Immune Response to Tumors

NK cells• are capable of destroying tumor cells without prior

sensitization

• After activation with IL-2 and IL-15, NK cells can lyse a wide range of human tumor cells

• recognizes stress-induced antigens that are expressed on tumor cells and cells that have incurred DNA damage and are at risk for neoplastic transformation

Immune Response to Tumors

• T cells, NK cells, and macrophages may collaborate in antitumor reactivity

• Interferon-γ, IL 2 secreted by T cells

• NK cells, is a potent activator of macrophages

Evasion of immune system by tumor cells

Lack of costimulatory signal • Sensitization of T cells requires two signals, one is

presented on MHC molecule complex and the other by costimulatory molecules (B 7).

• Due to the absence of both MHC and B 7 molecules, tumor cells provide very poor signal to APCs and consequently evade the immune system

Evasion of immune system by tumor cells

Decreased MHC I expression

• CD 8 CTLs are not able to bind and kill tumor cells

• Tumor cells with low MHC I expression escape from immune system and survive to grow

Immunodiagnosis• Tumor antigens useful as tumor markers released only from tumor tissue Specific for a given tumor type Has direct relationship to the tumor cell Present in all patients with tumor

• Tumors release antigen macromolecules that can be detected in vivo and in vitro

Immunodiagnosis

• Examples of tumor antigens used tumor markers • Alpha-Fetoprotein• Beta-subunit of human chorionic gonadotropin (B-HCG)• Prostate-specific antigen (PSA)• CA 125• Carcinoembryonic Antigen (CEA)

Immunodiagnosis

• Immunohistochemistry Categorization of undifferentiated malignant tumors Determination of site of origin of metastatic tumors Detection of molecules that have prognostic or

therapeutic significance

Immunotherapy

• Enhancement of tumor cell immunogenicity

1. Co- stimulatory signal : B 7 gene2. Good APC : GM CSF3. Cytokines : IFN alpha, beta, gamma; IL 1,2,4,5,12;

TNF

Immunotherapy

• Passive immunotherapy using monoclonal antibodies

1. Herceptin: anti-HER-2/neu in breast cancer patients

2. Rituximab: anti-CD20 in patients with non-Hodgkin’s lymphoma

Immunotherapy

• Active immunotherapy by using vaccines :

– HPV vaccines (e.g, cervarix); E6 E7 are combine with MHC and administered in host to boost the immunity against HPV infection

– Melanoma, colon ca, breast and ovarian ca, head & neck squamous cell ca, prostate ca

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