Chapter 20 Tumor Immunology

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Chapter 20 Tumor Immunology
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Chapter 20 Tumor Immunology
Contents

• Introduction
• Part? Tumor antigens
• Part? Immune response to tumors
• Part ? Mechanism of tumor escape from
• immune surveillance
• Part? Immunotherapy of tumors

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Introduction

• Tumor immunology is mainly to study the
  immunogenicity of tumor and the mechanism of
  immune response to tumor, to demonstrate the
  relationship between the status of immune system
  and the generation, development of tumor, to
  explore the method of tumor diagnosis, therapy
  and prevention.
• Immunosurveillance

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Part? Tumor antigens

• Tumor antigens Refer to all newly expressed
  antigens or over expressed antigens during the
  generation and development of the tumor.

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?.Classification of tumor antigens

• Base on their patterns of expression
• Tumor specific antigen (TSA)
• Tumor associated antigens (TAA)

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1.Tumor-specific antigens (TSA)

• TSA Antigens that are only expressed on tumor
  cells but not on normal cells. high specificity.
  
• Tumor high-specific antigens
• TSA---only expressed on one kind of tumor,
  induced by physiochemical factors, such as X-ray
• Tumor low-specific antigens
• TSA---expressed on more than one kind of
  tumor, induced by virus

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Discovery of tumor specific transplantation
antigens, TSTA
?????????(methyl-cholanthrene,MCA)
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Conclusion from this experiment

• Tumors express antigens that are recognized as
  foreign by the immune system of the tumor-bearing
  host.
• Immune response frequently fail to prevent the
  growth of tumors.
• The immune system can be activated by external
  stimulator to effectively kill tumor cells and
  eradicate tumors.

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2.Tumor-associated antigens,TAA

• Antigens that are also expressed on normal cells,
  but high expressed on tumor cells. Without tumor
  specificity CEA, AFP

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?.Common human tumor antigens

• Embryonic antigens
• Tumor antigens induced by viruses
• proteins coded by Mutated oncogene or suppressor
  oncogene
• TATAS expressed on human melanoma cells

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1. embryonic antigens

• embryonic antigens are proteins that are
  express at high levels on cancer cells and in
  normal developing fetal, but peter out or very
  low level in adult.
• Their main function is that they provide markers
  that aid diagnosis of tumor.
• Carcinoembryonic antigen (CEA)
• alpha-fetoprotein (AFP)

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(1) Carcinoembryonic antigen (CEA)

• High CEA level is normally restricted to cells of
  the gut, pancreas, and liver in the course of 2-6
  months of gestation, and low level is found in
  serum of normal adult(lt5?g/ml).
• CEA level of serum is increased in many
  carcinomas ,such as the colon, pancreas, stomach,
  and breast.
• The level of serum CEA is used to monitor the
  persistence or recurrence of the tumors after
  treatment.

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• CEA levels in normal individuals are below 2.5
  ng/ml, but it increases significantly in certain
  malignancies, particularly colo-rectal cancers.
  It may also rise in some nonmalignant conditions
  (e.g., chronic cirrhosis, pulmonary emphysema,
  heavy smoking). Levels 4-5-fold of normal have
  been used to predict recurrence of colo-rectal
  tumors.

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Carcinoembryonic antigenclinical use

• Adjunct in diagnosis
• Staging and prognosis
• Monitoring response to therapy
• Detection of tumor recurrence

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Carcinoembryonic antigenclinical use
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(2) alpha-fetoprotein (AFP)

• AFP is a circulating glycoprotein normally
  synthesized and secreted by the yolk sac and
  liver of fetal.
• Serum levels of AFP is very low in serum of adult
  (20ng/ml), and the concentration of AFP is up to
  500ng/ml in serum of patients with
  hepatocellular carcinoma.
• higher rise in this protein is used for
  monitoring hepatomas and testicular cancers. AFP
  level may also be raised in some nonmalignant
  conditions, such as cirrhosis, hepatitis and
  other forms of liver damage.

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Alpha fetoprotein concentrations

• Normal concentration lt20 ng/ml
• Abnormal concentrations
• 100-350 possible hepatoma
• 350-500 probable hepatoma
• 500-100 likely hepatoma
• gt1000 HEPATOMA

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• 2. Tumor antigens induced by viruses
• HBV------ liver cancer
• HPV------ cervical carcinoma
• EBV------ B cell lymphoma and
• nasopharyngeal carcinoma

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• 3. Products of mutated genes
• Some tumor antigens are produced by mutated
  genes, such as suppressor oncogenes p53 and
  pro-oncogene ras

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• Some patients with cancer have circulating CD4
  and CD8T cells that can respond to the products
  of mutated genes such as Ras and P53.
• Furthermore, in animals, immunization with
  mutated Ras or P53 proteins induces CTLs and
  rejection responses against tumors expressing
  these mutants.

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• Overexpressed cellular proteins and
• abnormally expressed proteins
• gp100, MAGE in melanomas
• Cancer-testis antigens

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Part? Mechanism Immune Response

• T cells aßT,
  ?dT
• NK cells
• Cellular immunity
• Macrophages
• Dendritic
  cells
• Humoral immunity

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?.Cell-mediated Immune Response

• T cells
• NK cells
• Macrophages(MF)
• Dendritic cells (DCs)

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• 1. T lymphocytes
• ??T cells
• The principal mechanism of tumor immunity is
  killing of tumor cells by CTL
• Tumor antigens
• DC cross presentation

CD4Th cells
CD8T
(CTL)
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• (2) ??T cells
• Non-class?MHC restriction
• Its target cells are not hypersensitive to NK
  cells
• First line of defence of immune surveillance

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• 2. NK cells
• NK cells are broad-spectrum killer cells
• It can kill target cells with low level or non
  MHC class ?molecule.
• First line of defence of immune surveillance

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NK????MHCI??????

KIR2DS KIR2DL
KIR2D KIR3D
DAP12 ITAM
????????????(KIR)(MHC-G)
ITIM
KIR2DL KIR2DS
CD94/NKG2AITIM CD94/NKG2C??DAP12 -ITAM
??????????(KLR) (HLA-E-9?)
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activated
Tumor cell
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• 3. Macrophages(MF)
• ? APC
• ? release of lysosomal enzymes, reactive
• oxygen intermediates, nitric oxide
• ? ADCC
• ? secrete cytokines
• 4. Dendritic cells
• ? APC------Induce adaptive immune response
• ? Inhibit tumor growth directly

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Antibodies ? Activating complement ? ADCC?
Opsonization
?. Humoral immune responses
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Antitumor Effector Mechanisms
CTL
NK cell
Tumor cell
Humoral Mechanisms
Macrophage
Kumar et al. Basic Pathology 6th ed. Figure 6-32
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Part? Mechanism of Tumor Immune Escape

• Factors related to tumor cells
• Factors related to the hosts
• immune system

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?. Factors related to tumor cells

• 1.low immunogenicity of tumor antigens and
  antigenic modulation
• (1) low immunogenicity of tumor antigens
• The failure of immunosurveillance may be the
  fact that in the early development of a tumor,
  the amount of antigen may be too small to
  stimulate the immune system.

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Escape from immunosurveillance
Lack of Neo-antigens
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• (2) antigenic modulation is a phenomenon that
  cell-surface tumor antigens are decrease or lose
  because of attack of hosts humoral immune.

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• 2. covering or blocking of tumor antigens on the
  surface of the tumor cells

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• 3. Diminution or absence of MHC class I molecule
• 4. Lack of co-stimulatory molecule on the surface
  of tumor cells
• 5. Immune inhibitors secreted by tumor cells

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Escape from immunosurveillance
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?.Factors related to hosts immune system

• 1. Immunodeficiency
• 2. Suppressing immune function by tumor directly
  or indirectly

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Parts ? immunotherapy of tumor

• Active immunotherapy
• Target immunotherapy
• Adoptive immunotherapy
• Cytokine therapy
• genetherapy

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Escape from immunosurveillance
Tumors shed their neo-antigens
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• Factors related to host
• Poor immune function
• Tumor inhibit immune function of host

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Escape from immunosurveillance
Tumors secrete Immunosuppressive molecules
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Part? Immunotherapy of tumors

• Active immunotherapy
• Target immunotherapy
• Adoptive immunotherapy
• Cytokine therapy
• Gene therapy

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• Stimulation of active host immune
• responses to tumors
• Vaccination with tumor cells and tumor antigens,
  or with APC.
• Augmentation of host immunity to tumors with
  cytokines and costimulators
• Nonspecific stimulation of the immune system

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• Vaccination with tumor cells and tumor antigens

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• DC
• Use primed dendritic cells
• APCs can be fed tumor antigens in the laboratory
  and then injected into a patient. The injected
  cells are primed to activate T cells
• Alternatively, DCs can be infected with a viral
  vector that contains the gene for a tumor
  antigen.

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Use of tumor specific/associated antigens
monoclonal antibodies
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• Adoptive immunotherapy
• Adoptive cellular immunotherapy is the
  transfer of cultured immune cells that have
  anti-tumor reactivity into a tumor-bearing host.
• LAK, TIL, CD3AK, CTL

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• Passive immunotherapy for tumors with
• T cells and antibodies
• Therapy with anti-tumor antibodies
• Monoclonal antibodies conjugated drugs
• Adoptive cellular therapy
• LAK,TIL,CD3AK,CTL

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• Cytokines may also be administered systemically
  for the treatment of human tumors.
• IL-2 works by stimulating the proliferation and
  anti-tumor activity of NK cells and CTLs.
• IFN-?works by increasing the cytolytic activity
  of NK cells and class I MHC expression on various
  cell types.
• Their side effects limited this treatment.

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• Augmentation of host immunity to tumors with
  cytokines and costimulators