Tumor Immunology

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Tumor Immunology
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Key questions

• How do tumor cells evade the immune system
• What are the main immune responses to tumor
  cells?
• What are the potential anti-tumor
  immunotherapies?

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23. Tumor Immunology
CORE

• a. Properties of tumor (transformed) cells
• (1) Abnormalities in growth and responses to
  regulation and apoptosis
• (2) Induction by carcinogens, viruses
  spontaneous
• (3) Role of oncogenes (e.g. growth-promoting
  oncogenes and oncoproteins)
• (4) Role of tumor-suppressor genes and genes
  that control DNA repair

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Cancer Cancer is caused by abnormal and invasive
growth of tumor cells It accounts for 20 of
death in industrialized countries. 6 million new
cancer patients each year worldwide. Generally,
cancer occurs late in life. Caused by accumulated
mutations in the genes controlling cell growth
and death. Current treatments surgery,
radiation and cytotoxic drugs Future treatments
small molecule drugs that specifically inhibit
tumor cell growth immunotherapy
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Carcinogens induce mutations in DNA Chemical
carcinogens Radiation Oncogenic viruses (
chronic infection/inflammation)
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Accumulation of mutations leads to cancer cells
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The growth and lifespan of a typical human tumor
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Benign vs. malignant tumors Breast tumors for
example
Malignant cells are more aggressive in growth,
and they spread to nearby tissues or to different
organs through lymph and blood vessels
(Metastasis)
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Terminologies

• Carcinoma epithelial cell tumors
• Leukemia tumors of circulating cells
• Lymphoma solid tumors in lymph nodes
• Myeloma tumors of bone marrow cells
• Sarcoma tumors of connective tissue cells

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Viruses are associated with some human cancers
Some viral proteins induce unchecked
proliferation of human cells by targeting genes
such as P53 and Rb
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Can tumor cells from a person grow in another
person?
Usually, no. But sometimes, yes. Largely, it
depends on the MHC haplotype of donors and
recipients.
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How do immune cells detect tumor cells? CD4,
CD8, NK cells and B cells
They look for tumor antigens, antigens
differentially expressed by tumor cells and
normal cells.
Tumor antigens Changes in the genome of tumor
cells can lead to the expression of tumor
antigens, which are not (tumor-specific antigens)
or less expressed in normal cells
(tumor-associated antigens) .
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b. Tumor-specific and tumor-associated antigens
CORE

• (1) Tumor-specific shared antigens melanoma
  antigen-1 (MAGE-1) found on melanomas and other
  transformed cells
• (2) Tissue-specific antigens (on normal and
  transformed cells such as tyrosinase found on
  normal and transformed melanocytes)
• (3) Antigens resulting from mutation (such as
  mutations of oncogenes)
• (4) Over expressed antigens antigens expressed
  at abnormal stage of development
• Viral antigens
• Other cancer indicators
• (a) Oncofetal antigens
• Carcinoembryonic antigen (CEA) Colon cancer
• Alpha-fetoprotein Liver and testis cancer
• (b) Differentiation antigens
• Common acute lymphoblastic leukemia antigen
  (CALLA, also called CD10) found on cells of
  acute lymphoblastic leukemia
• PSA (Prostate cancer)

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Tumor antigens Qualitative and/or quantitative
changes in antigen
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Tumor antigens
Tumor Epitope Escape

• Mutation of anchor residues
• Mutation of TCR contact residues
• No CTL recognition
• Antagonistic Epitope gt negative signal to CTL
  (Altered Peptide Ligand APL)
• Mutation affecting antigen processing
• Within epitope affecting stability of epitope
• Outside of epitope efficiency of epitope
  processing

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Examples of tumor antigens recognized by CD8 T
cells
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c. Anti-tumor immunity
CORE

• (1) CMI (TC, TH1 cytokines, NK, macrophage)
• (2) Humoral (ADCC and activation of complement)
• (3) "Immunosurveillance" There is an increased
  frequency of cancers in immunocompromised
  individuals, however, most cancers occur in
  individuals with no overt immunodeficiency. More
  likely that tumors develop ways of evading the
  immune system.

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Anti-tumor immunity Cell-mediated immune
response CD4 T cells control other immune
cells by cytokines CD8 T cells direct lysis NK
cells direct lysis Eosinophils
degranulation Humoral response by B
cells Antibodies to tumor cells 1. facilitate
NK cell-mediated lysis of tumor cells 2. activate
complement reaction
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NK cells can attack tumor cells lacking MHC I
expression
tumor cells
NK cells
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Tumor antigen specific CD4 and CD8 T cells
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Figure 12-52
DCs present tumor antigens to CD4 and CD8 T
cells. Membrane fusion allows presentation of
tumor Ag to CD8 T cells.
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CORE
How do tumors evade immune responses?

• Examples of tumor evasion
• out-growth of antigen-negative variants
• loss or reduced expression of MHC proteins
• secretion of immunosuppressive cytokines
• (d) inducing CTL apoptosis
• (e) lack of co-stimulatory signals
• soluble tumor antigens

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• Mechanisms of tumor cell evasion of anti-tumor
  cells
• Defective in one or more of their MHC class I
  expression
• (30-50 of tumors are defective in MHC I
  expression)
• Production of suppressive cytokines (TGF-beta and
  Th2 cytokines), which suppress cell-mediated
  immune response
• Lack of co-stimulatory signals
• Out-growth of antigen-negative variants
• Shedding of MHC class I-related chain (MIC), a
  ligand of NKG2D that is an activating NK cell
  receptor, by epithelial tumor cells to inhibit
  NKG2D NK cells

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Figure 12-50
Loss of MHC class I expression in prostate tumor
cells
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d. Immunotherapy
CORE

• (1) Non-specific stimulation (adjuvant therapy)
• (2) Active immunization with tumor antigens
  role of co-stimulatory molecules
• (3) Cytokine therapy
• (4) Adoptive cellular immunotherapy (LAK cells,
  TIL)
• (5) Anti-tumor antibodies (coupled to cytotoxins
  or radioisotopes)

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Non-specific adjuvant therapy Introduction of
BCG vaccine (killed mycobacterium) into the
bladder is a treatment for superficial bladder
cancer This may be because Bacterial products
or adjuvants increase the T cell response by
activating antigen presenting cells and other
cells through TLRs. This will also induce
co-stimulation molecules and MHC molecules on
APCs.
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• Potential immunotherapies against tumor cells
• Antibody against tumor antigen (immunotoxins and
  induction of ADCC by NK cells).
• Tumor vaccines tumors taken at surgery are
  manipulated ex vivo (out of body) and are used as
  vaccine. This manipulation includes expressing
  B7, GM-CSF or IL-12 in tumor cells. Tumor
  antigens can be used as vaccines too. e.g. CEA
  (carcinoembryonic antigen), HSP (heat shock
  protein), and telomerase.
• Dendritic cell therapy dendritic cells are
  isolated from patients and are loaded with tumor
  antigen peptides in vitro. These cells are
  injected into patients to boost anti-tumor T cell
  response.
• T cell therapy patients T cells, activated in
  vitro with tumor antigens and cytokines (IL-12),
  are injected back to the patients.

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Monoclonal antibodies for cancer therapy Rituxan.
Anti-CD20, a cell surface marker found on most B
cells. Certain non-Hodgkins lymphomas. Herceptin.
Anti-EFG-receptor-2 (also known as HER2, ErbB2
or Neu), which is overexpressed in 25 percent of
breast cancers. Erbitux, anti-EGFR (HER1),
approved for metastatic colorectal
cancer Avastin. Blocks the vascular endothelial
growth factor (VEGF) receptor. An
anti-angiogenesis drug. Radiolabeled
MAbs Zevalin- A radiolabeled MAb to treat B cell
non-Hodgkin lymphoma that has not responded to
standard treatment. Bexxar - A radiolabeled MAb
to treat certain types of non-Hodgkin lymphoma
that no longer respond to rituximab (Rituxan) or
chemotherapy. Radiolabeled antibodies approved
by the FDA to detect cancer. OncoScint (for
colorectal and ovarian cancer) ProstaScint (for
prostate cancer).
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Figure 12-49
Immunization with MAGE-1/3 induces anti-melanoma
immune response
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Monoclonal antibodies to tumor antigens can
deliver toxins or NK cells to tumor cells