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Neoplasia lecture 10
Dr Heyam Awad
TUMOR IMMUNITY
• Tumor cells are recognized by the host ( the body) as non self.
• Once recognized, immunologic reactions are activated to destroy the
tumor cells.
• This process is called immune surveillance
• However, immune surveillance is imperfect and that’s why tumors still
occur i:e some of the tumor cells escape destruction by the immune
system.
• Immune system recognizes cells by their antigens.
• If cells express antigens that are perceived by immune cells as non
self , the immunologic reaction starts
• So: what are the antigens present on the cancer cells?
Tumor antigens
• Two types f tumor antigens: tumor specific and tumor associated
antigens
• Tumor specific antigens: specific to the tumor and not seen in normal
cells
• Tumor associated antigens: present on tumor cells and normal cells
but are mutated or overexpressed in cancer cells
Products of mutated oncogenes or tumor
suppressor genes
• Mutated genes are translated to abnormal proteins that are non-self
• Examples: p53, RAS, B catenin
• Sometimes the gene product is not mutated but overexpressed like
HER2/NEU
Products of other mutated genes
• In cancer cells genomic instability results in mutations in any gene (
some are non- carcinogenic genes).. Which might encode an
abnormal protein
Overexpressed cellular protein
• Some tumor antigens are normal proteins present normally in cells
in low concentration without eliciting immune response. BUT in
tumors these are present at high concentration and can cause
immune reaction
• Example: tyrosinase in melanoma
Abnormal expression of a cellular protein in
an abnormal location
• Some proteins are normal and found only in certain cells. In cancer
these proteins are expressed in abnormal sites and can be recognized
as non-self.
• Example: cancer-testis antigens…. These are normally expressed only
in testis .
• The cancer testis antigens include several proteins: MAGE< GAGE<
BAGE.
Antigens produced by antigenic viruses
• HPV, EBV can produce proteins like E6 and E7
Oncofetal antigens
• These are proteins expressed only in embryos
• In some tumors ( mainly colon and liver) they are re-expressed
• examples: CEA= carcino-embryonic antigen and alpha fetoprotein
• These are important serum markers of cancer
Altered cell surface glycolipids and
glycoproteins
• Include: mucins, blood group antigens and gangliosoids
• CA 125 and CA 19-9 are altered mucin proteins , mainly in overian
carcinoma
• MUC 1 is altered mucin in breast carcinoma
• MUC 1 normally found in apical surface of epithelial breast cells ..so
can not be “seen” by the immune system…. In cancer this MUC 1 is
present in the surface as well, so can be recognized.
Cell type specific differentiation antigens
• These are proteins present normally in some cells and dictate their
differentiation
• B lymphocytes express CD20 . It is also expressed in B cell lymphomas
• CD20 is not immunogenic.. But is important for diagnosis
• If you have a lymphoma you can know it is of B cell origin if it
expresses CD20
Anti-tumor mechanisms
• Cellular immunity plays a role in immune surveillance
• Humoral immunity ( antibodies, B lymphocytes and plasma cells)
don’t play a role in vivo
Anti-tumor mechanisms
• The cells responsible for immune surveillance are:
• 1. cytotoxic T lymphocytes
• 2. Natural killer cells
• 3. macrophages
Cytotoxic T cells ( CD8 positive lymphocytes)
• Need specific sensitization
• Play a role mainly in virus associated cancer
• Can recognize cells expressing major histocompatibility complexes
(MHC)
Natural killer cells
• No need for presensitization
• Activatd by IL2
• They lyse tumor cells.. They target cells that don’t have MHC
• If tumor cell expresses MHC, it will be a target for cytotoxic T cell, if
no MHC it will be targeted by natural killer lymphocyte
note
• Natural killer cells have two types of receptors.. Ones that recognize
MHC , and these inhibit natural killer cells…. The other receptors act
on cells that have no MHC ( these receptors recognize stress induced
antigens caused by DNA damage)
macrophages
• M1 macrophages are cytotoxic to some cells
• They kill by: ROS or by TNF
• Cytotoxic T and Natural killers secrete interferon gamma that
stimulates macrophages
Immune evasion
• Immune surveillance is important in protecting the host from cancer .
• Immune- compromised individuals have increased risk of developing
cancer
• One of the hallmarks of cancer is evasion of destruction by the
immune system
Mechanisms of evasion of the immune
system
• 1. selective growth of antigen negative variants ( subclones ). The
highly antigenic subclones are deleted from the tumor mass
• 2. loss or reduced expression of histocompatibility molecules.
• 3.downregulation of co-stimulatory molecules
• 4. antigen masking by producing a thick coat of external glycocalyx
molecules
• 5.immunosuppression ( see next slide)
immunosupression
• Tumor cells can suppress host immunity by:
• A. TGF beta production by tumor cells
• B. expression of fas ligand that binds to fas receptor on host
lymphocytes causing apoptosis of these lymphocytes
• C. some oncogenic agents suppress host immunity, especially
chemicals and ionizing radiation.
Clinical aspects of neoplasia
• Tumors affect patients by:
• 1. their location
• 2. hormonal secretions
• 3. paraneoplastic syndromes
• 4. bleeding and infection
• 5. rupture or infarction
• 6. cachexia
Tumor location
• Even small tumors can be dangerous
• CNS tumors can cause increased intracranial pressure
Effects of tumors on the host/ location effect
Effects by hormonal secretions
example pituitary adenoma can secrete ACTH and
cause Cushing syndrome
Cancer cachexia
• = progressive loss of body fat with associated weakness, anorexia and
anemia
• Cachexia is not caused by the nutritional demands of the tumor
• There is some correlation between cachexia and the size and extent
of spread f the cancer.
Causes of cachexia
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Anorexia plays a role, however chemical factors are the main reason
Cachectic patents have high metabolic rate, muscle wasting
TNF produced from macrophages is probably the main factor for these changes
Effects of TNF:
1. suppresses appetite
2.inhibits lipoprotein lipase
ALSO: proteolysis inducing factor that breaks skeletal muscle by ubiquitin
proteasome pathway is increased in cancer patients… it causes muscle wating
Cancer cachexia
• The only satisfactory treatment of cancer cachexia is removal of the
primary tumor
Para-neoplastic syndromes
• = symptoms that cannot be explained by local or distant metastases
or by hormones endogenous to the site of origin.
• These are usually caused by ectopic hormone secretion
• Most common para neoplastic syndromes: hyercalcemia, Cushing
syndrome, and nonbacterial thrombotic endocarditis
• Most common tumors that are associated with paraneoplastic
syndromes: lung, breast and hematologic malignancies
Hyercalcemia as paraneoplastic
• Caused by
• 1. PTHrP ( parathyroid hormone related protein)
• 2.TGF alpha activate osteoclasts and the active form of vit D
• 3.TNF and IL1
• NOTE: Skeletal mets cause hyperkalemia but this is not a
paraneoplastic syndrome
Paraneoplastic syndromes
Para- neoplastic syndromes
Clubbing of fingers is paraneoplastic, mainly
due to lung cancer… etiology is unknown
Grading and staging of cancer
• Grading is determined by cytologic and histologic appearance of the
tumor
• In general well differentiated tumors are less aggressive than poorly
differentiated ones
• However.. Staging is more important than grading in determining
outcome and prognosis
Well differentiated adenocarcinoma.. Note
the glands
Grading of tumors
• Poorly differentiated adenocarcinoma.
staging
• TNM classification
• T.. Tumor size OR extent of invasion of the wall
• N.. Lymph node involvemevt
• M … metastasis
• Each tumor type has different criteria for its TNM staging
Staging of tumors