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Ch. 21. Cancer and the Immune System
What is cancer?
What is the immune response to cancer?
What are the prospects for immune therapies?
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Cancer cells are out of control!
Usually derived from a single cell, forminga neoplasm, or tumor
Benign tumors are noninvasive; malignant tumors can invade and spread(metastasis)
Cancers are classified according to their originCarcinomas vs blood cell cancers:
leukemias and lymphomas
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How do cells become “transformed” intomalignant cells?
RadiationCarcinogensViruses
expression of oncogenes (aberrant versions of proto-oncogenes)
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Types of regulatory genes
Proto-oncogenes- induce proliferation invarious ways
Tumor suppressors- inhibit cell proliferation
Regulators of apoptosis
Defects in any of these can lead to uncontrolledcell growth
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Mutations accumulate in these cells as theyare gradually converted to malignantcells
Translocations are associated with certainspecific tumors
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Immune system tumors
Solid or systemic?Acute or chronic?Immature or mature cells?Myelocytic or lymphocytic?
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Tumor-specific antigens (TSTA) - found only on tumorschemical or physical carcinogenssome viruses: e.g., ATLL, HPV
Adult T-Cell Leukemia/LymphomaHuman Papilloma Virus (types 16 & 18)
Tumor-associated antigens (TAA) - may be gene products that normally are not expressed(or at the abnormal levels seen in cancer)
Can these be isolated and used as vaccines?Diagnosis? Therapy?
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Most tumor antigens are NOT unique to tumors
Often these are fetal proteins (e.g., growth factor receptors)
CEA- carcinoembryonic antigenAFP- alpha-fetoprotein
Oncogene proteins as tumor antigensNeu on human breast cancer cellsTATA’s on human melanomas: MAGE1,
MAGE-3, BAGE, GAGE-1, GAGE-2. Some shared with other tumors
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Immune response to tumors: Ab’s & CMI (after all, it’s altered self)
Cell-mediated response of major importance: CTL’s, NK cells (with or w/o ADCC), activated macrophages ~ regression (lytic enzymes, ROI, RNI, TNF-alpha)
Many tumors reduce MHC Class I expressionNK cells can kill these
Also macrophages add NK cells can attackantibody-coated tumor cells (ADCC)
Immune surveillance?
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Tumors can evade immune response
Anti-tumor antibody can block T cell responses(enhance tumor growth)
Tumors can modulate antigens – “Ag modulation”(Ab’s bind to Ag on leukemic cells, induce capping, endocytosis of Ag, shedding of Ag-Ab complexes)
Tumors can reduce MHC Class I expression(selection; escape CTL recognition)
Tumors can reduce “second signal” expression(no B7 -> clonal anergy)
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Strategies for immunotherapy: adjuvant or cytokine
Make cells more immunogenicbetter CTL activation“vaccine” made up of cells?
Enhancement of APC activity can modulate tumor immunityBCG – attenuated Mycobacterium bovismouse dendritic cells incubated with GM-CSF
and tumor fragments, then into animal,activate anti-tumor Th and CTL’s
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Cytokine therapy
Many have been tried: thanks to recombinant DNA technologyinterferons (incr. MHC I, MHC II), tumor necrosis factors (TNF), IL-2, -4, -6, -12; GM-CSF
Problems:complexity of cytokine interactionshard to administershort half-lifeserious side effects
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LAK cells (lymphokine-activated killer cells)grow blood cells in high levels of IL-2produce mostly NK cells (NOT tumor-specific)
TIL’s (tumor-infiltrating lymphocytes)may have more tumor-specific activityand need less IL-2
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Monoclonal antibodies are useful in treating some tumors
Idiotype-specific for B-cell lymphoma: Levy (Stanford)
Humanized
Anti-HER2 for HER2-receptor-bearing breast cancer
Immunotoxins – mAb conjugated to ricin
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Cancer vaccines?
Antigenic peptides (tumor-specific and immunogenic
Delivery (recombinant vaccines)
Will they be effectively presented to T cells?
Some viral vaccines (e.g., against HPV)may be helpful
There is much to be done.