Transcript Tumor immunity

Tumor immunity
Overview
• Introduction
• Tumor antigens
• Immune response
• Evasion of immune responses by malignant cells
• Immunotherapy
• Summary
A fight between immune cells and cancer
But, sometimes we lose
• The idea that tumors are recognized by
the immune system was first given by Paul
Ehrlich
Evidence for immunity to tumor
• Tumors that have severe lympho-reticular
infiltration have a better prognosis.
• Certain tumors regress spontaneously
(e.g., melanomas, neuroblastomas).
• Increased incidence of malignancies
(lymphoma) in immunodeficient patients.
Immune reactivity to tumor
• Antibodies and immune T lymphocytes (in
cytotoxicity and mitogenic response
assays) detected in patients with tumors.
• Animals can be specifically immunized
against various types of tumors.
• Cancer immunoediting
– Is the term used to describe the effects of
immune system in preventing tumor formation
and also the properties of tumor cells to
escape immune recognition
• Tumor immunity
– Tumor Antigens: Earlier classified as tumor
specific and tumor associated antigens
Tumor associated antigens
TAAs
• In order for the immune system to react
against a tumor, they must have antigens
that are recognized as foreign.
Tumor associated antigens
TAAs
• A number of alterations occur in the cell
during tumorigenesis (e.g., enzymes,
receptors, membrane antigens, etc.).
Tumor immunity
Tumor Antigens: Earlier classified as tumor specific
and tumor associated antigens.
Now classified according to molecular structure and
source.
• Products of mutated oncogenes and suppressor genes.
• Products of other mutated genes as in radiation
• Over-expressed self proteins
• Tumor antigens produced by oncogenic viruses
• Oncofetal antigens - expressed normally in fetus
• Altered cell surface glycoproteins and glycolipids
• Cell type differentiation antigens
Tumor antigens
• mutations
• abnormal expression
• oncogenic viruses
• oncofetal antigens
• altered surface modifications
• tissue specific differentiation antigens
Oncofetal antigens
• These are proteins that are expressed at high
levels on cancer cells and in normal fetal
tissues, but not on adult tissues
• Oncofetal antigens may appear due to derepression of preexisting genes.
Two major oncofetal antigens are:
Alpha-fetoprotein (AFP)
Carcinoembryonic antigen (CEA)
Overview
• Introduction
• Tumor antigens
• Immune response
• Evasion of immune responses
• Immunotherapy
• Role of immune system in promoting tumor growth
• Summary
Immune responses to tumors
• innate immune responses
• NK cells
• macrophages
• adaptive immune responses
• T cells
• antibodies
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© 2005 Elsevier
• Natural killer (NK) cells
They directly kill tumor cells, helped by
interferon, IL-2
• Macrophages
Production of antibodies by B-cells :
• Tumor associated antigens stimulate
production of specific antibodies by host Bcells
• These specific antibodies bind to tumor cell
leading to destruction of tumor through:
•
•
a- Antibody mediated-cytotoxicity :
b-Activation of complement
Mechanisms by which tumours escape the immune
system:
• Selective overgrowth of antigen negative variants
• Loss / reduced MHC expression
• Lack of co-stimulation
• Immunosuppressive cytokines
• Antigen masking
• Apoptosis of cytotoxic T cells
Tumor Escape
Mechanisms by which tumor escape immune defenses:
1) Reduced levels or absence of MHC molecule on tumor so
that they can not be recognized by CTLs
2) Some tumors stop expressing the antigens
These tumors are called “antigen negative variants”
3) Production of immunosuppressive factors by tumor e.g.
transforming growth factor (TGF-β)
4) Apoptosis of cytotoxic T cells
Tumor Escape
5) Tumor cells have an inherent defect in
antigen processing and presentation
7) Antigens on the surface of tumors may be
masked by sialic acid-containing
mucopolysaccharides (glycocalyx
molecules). eg: CA-125, CA19-9,CA15-5
Immunotherapy
• A variety of immunopotentiating agents are
used to enhance anti-tumor immunity.
• They include bacterial products, synthetic
chemicals and cytokines.
• These exert their effects by activating
macrophages and NK cells, eliciting
cytokines or enhancing T-cell functions.
Immunotherapy to Tumors
nonspecific
BCG, levamisole, cytokines.
specific
Killed tumor cells or their extract,
Recombinant antigens, co-Stimulatory
molecule genes, etc.
Active
Passive specific
Antibodies (Monoclonal) alone or
coupled to: drugs, radioisotope
Summary
• tumor antigens are recognized by immune system
• immune response mainly mediated by CTL, NK cells and
macrophages
• immune evasion tumor cells
• immunotherapy aims at activating the patient’s own
immune system to fight the tumor