Tumor immunity
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Transcript of Tumor immunity
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
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