The Immune System and Cancer

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The Immune System and Cancer
Session Objectives 1. Describe the role of the
immune system in cancer and how tumours may
escape such surveillance 2. Have a working
knowledge of the potential importance of
immunology in diagnosis and therapy of
cancer 3. Describe the role of specific viruses
associated with human cancers, using cervical
cancer as a case history
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The Immune System and Cancer

• Lecture Objectives
• By the end of the lecture you should be able to
• Describe different types of tumour antigens
• List ways in which tumours escape the immune
  system
• Describe two ways in which antibodies can be used
  in immunodiagnosis
• Describe the current strategies used in
  immunotherapy

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How do we know that the immune system plays a
role in controlling tumours ? (Immune
Surveillance)

• Evidence from
• Patients receiving immunosuppressive drugs for
  transplants
• Patients with immunosuppressive viruses eg. HIV
• Role for T cells in animals carrying
  virus-induced tumours

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T cells in Carcinoma of the Breast
CD4 T cells
CD8 T cells
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For the immune system to deal with tumours, they
first have to recognise them as foreign (like any
microbe) PROBLEM Tumours cells are SELF
and therefore the immune system is tolerant of
most of their components. However there are
some components that are recognised by the immune
system - The Tumour antigens
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Tumour Antigens

• Tumour Specific Antigens (TSA) - unique
  to tumour cells - rare
• 1) derived from mutations resulting in
  altered cellular proteins as novel proteins
  they would induce an immune response
• Tumour Associated Antigens (TAA) - more
  common
• 1) virus specific
• 2) oncofetal antigens
• 3) differentiation antigens
• 4) antigens overexpressed in particular tumours

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Tumour specific antigens
Chemically induced antigens Because of random
mutagenesis of DNA, chemically induced tumours
often express antigens unique to the individual
tumour
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Tumour Associated Antigens
1. Virally induced tumour antigens Oncogenic DNA
and RNA viruses code for these - shared by all
tumours induced by the same virus
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Viruses associated with human tumours
Tumour virus Human tumour Human T-cell
lymphotrophic virus Adult T cell
leukaemia/ (HTLV) lymphoma Hepatitis B virus
(HBV) Liver cancer Human papilloma virus
(HPV) Cervical/anal/ pharyngeal
cancer Epstein-Barr virus (EBV) Lymphomas/
nasopharyngeal cancer
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Tumour Associated Antigens
2. Oncofetal antigens Frequently associated with
normal cells during development
antigen fetal tissue associated
tumour Carcinoembryonic Ag (CEA) Gut,
liver Gastrointestinal, breast Alpha- fetoprotein
(AFP) Liver, yolk sac Liver
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Tumour Associated Antigens
3. Differentiation antigens Found in normal
cells during during specific stages of cellular
differentiation. (Can be used in tumour
classification of leukaemias)
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Differentiation antigens on lymphoid and myeloid
malignancies
eg. Acute Chronic Disease Markers Disease
Markers Common ALL CD10, CD19 B-CLL
CD19, CD20 Myeloid leukaemia
CD13, myeloperox
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Tumour Antigens
4) antigens overexpressed in particular
tumours eg. Prostate specific antigen -
PSA
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Identification of potential new tumour antigens
using sera from tumour patients SEREX Serological
analysis of human tumour antigens by recombinant
cDNA expression cloning Isolation of antigens
detected only by a high level of IgG or IgA
will not detect carbohydrate antigens 900 gene
sequences have so far been cloned using this
method - data bas set up.
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Potential immune mechanisms against
tumours (similar to microbial immunity)

• Antibody and complement
• Antibody dependent cellular cytotoxicity (ADCC)
  mediated by macrophages, PMNs and NK cells -
  through Fc receptors
• Natural Killer Cells
• Specific cytotoxic T cells - mainly CD8
  recognising tumour peptides associated with MHC
  class I These would be very useful and

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Antibody mediated killing of microbes
Same mechanisms for killing tumour cells
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Potential immune mechanisms against
tumours (similar to microbial immunity)

• Antibody and complement
• Antibody dependent cellular cytotoxicity (ADCC)
  mediated by macrophages, PMNs and NK cells -
  through Fc receptors
• Natural Killer Cells
• Specific cytotoxic T cells - mainly CD8
  recognising tumour peptides associated with MHC
  class I

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Antibody Dependent Cellular Cytotoxicity
Tumour cell
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Potential immune mechanisms against
tumours (similar to microbial immunity)

• Antibody and complement
• Antibody dependent cellular cytotoxicity (ADCC)
  mediated by macrophages, PMNs and NK cells -
  through Fc receptors
• Natural Killer Cells
• Specific cytotoxic T cells - mainly CD8
  recognising tumour peptides associated with MHC
  class I

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NK cell killing a virus infected cell
NK cell
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Potential immune mechanisms against
tumours (similar to microbial immunity)

• Antibody and complement
• Antibody dependent cellular cytotoxicity (ADCC)
  mediated by macrophages, PMNs and NK cells -
  through Fc receptors
• Natural Killer Cells
• Specific cytotoxic T cells - mainly CD8
  recognising tumour peptides associated with MHC
  class I

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Cytotoxic T cells (CD8)
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Cell mediated Immunity
Th
Help macrophages and B cells
Kill virus infected cells
Tc
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Tumour escape mechanisms

• Tolerance to tumour antigens
• Selection of tumour negative variants
• Antigenic modulation by antibodies

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Tumour escape mechanisms

• Tumour may produce immunosuppressive
  molecules
• (eg. IL10 and TGFb
• Reduced expression of MHC class I
• Tumour may express Fas ligand

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Immunodiagnosis

• Tumour monitoring
• - Detection of antigens in the blood
• - Detection of micrometastases
• Imaging
• (Monoclonal antibodies are used)

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Tumour monitoring
Used to detect the rate of change of TAA within
the serum of patients. Antigens Tumour Carcin
oembryonic antigen (CEA) Gastointestinal
Prostate specific antigen (PSA) Prostate Alpha
fetoprotein (AFP) Liver Mucins
CA-125/19-9 Ovarian (Can be detected in
other conditions).
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Measurement of CEA in the serum
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Tumour Imaging
Radioconjugated mABs specific for appropriate TAA
can sometimes be used to locate and image
metastases eg. mAb anti CEA labelled with 131I
injected intravenously images sites of metastases
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Carcinoma of the Colon
Chest radiograph showing lung metastases
Immunoscintigraphy
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Immunocyto/histochemistry
HRP horse radish peroxidase AP- alkaline
phosphatase
antigen
Mab labelled with an enzyme (eg. HRP,AP)
Colour change seen, red,blue,brown etc
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Identification of the cell of origin of an
undifferentiated tumour
mAb to B cell marker (CD20) labelled with enzyme
B cell lymphoma
Unidentified tumour cells
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Detection of carcinoma micrometastases in lymph
node imprint
Stained with mAb to cytokeratin commonly
expressed by carcinoma cells
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Immunotherapy
Several kinds are currently in use and being
developed

• Passive treatment
• Treatment with antibodies
• Treatment with cells
• Treatment with cytokines
• Active immunization

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Immunotherapy of tumours with antibodies
Some successful ones in clinical trial Anti
HER2/neu (herceptin) Breast Carcinoma Anti
CD20(Rituxan) B cell tumours Anti
17-1A Colorectal cancer
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Immunotherapy of tumours with antibodies
Most monoclonal antibodies are not tumour
specific but directed to TAA Problems - HAMA
response (Human anti mouse antibody) - Antige
n free in the serum - Selection of non-antigen
containing tumour cells Some are in clinical
trials
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Antibody based tumour therapy
Ab alone
Ab with toxins/radioisotopes
Bispecific antibodies
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Therapy with LAK cells and TILs
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Active immunisation
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Tumour Vaccines

• Two main kinds of vaccines
• Prophylactic
• These include virus associated tumours - antigens
  known
• (clinical trials of HBV and HPV)
• Therapeutic
• Peptides - aim to induce specific cytotoxic T
  cell responses
• (MHC class I restricted)
• DNA vaccines

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Dendritic cell vaccines
From Lydyard,Whelan and Fanger Instant Notes in
Immunology 2nd edition 2003
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The Immune System and Cancer

• Lecture Objectives
• By the end of the lecture you should be able to
• Describe different types of tumour antigens
• List ways in which tumours escape the immune
  system
• Describe two ways in which antibodies can be used
  in immunodiagnosis
• Describe the current strategies used in
  immunotherapy

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Cancer Biology