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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.