Download Tumor Specific Antigens

Host Defense Against Tumor
Tumor Immunity
Definition •
coordinated biologic process
designed to recognize tumor
cells and their products and to
kill or damage the offending
cells.
Host Defense Against Tumor
Tumor Immunity
• Tumor Specific Antigens (TSA)
Present only on tumor cells and
not on any normal cells and can be
recognized by cytotoxic T-lymphocytes.
• Tumor Associated Antigens
(TAA)
Not unique to tumors and are
also see on normal cells.
Tumor Antigens
• Tumor Specific Antigens (TSA)
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Cancer testis antigen
Viral antigen
Mucin
Oncofetal antigens
Antigens resulting from mutational in protein
B catenin, RAS, P53,CDK4
Tumor Antigens
• Tissue Associated Antigen=TAA
Present in normal cells & tumor cells
e.g. MART-1, gp100, tyrosinase expressed
in melanomas & normal melanocytes
T-cells directed against melanomas will
also destroy normal melanin containing
cells
Tumor Antigens
Tumor Associated Antigens(TAA)
• MART-1, gp100, tyrosinase
• Over expressed antigens
• Differentiation- specific antigens
Tumor Associated Antigens(TAA)
• Over expressed Antigens
e.g HER-2
(neu) in 30 % Breast
cancer
( present in normal breast & ovary)
Tumor Associated Antigens(TAA)
• Differentiation- Specific
Antigens
e.g CD10& PSA
Expressed in normal B
cells & Prostate
Used as a marker for tumors
arise from these cells
ANTITUMOR EFFECTOR
MECHANISM
Cellular
• Cytotoxic T lymphocytes.
• Natural killer cells.
• Macrophages.
Humoral
mechanisms.complement
mediated or ADCC.
Mechanisms of Immunity to
Tumors
• Cytotoxic T lymphocytes (CTL) that are sensitized to TSA and perhaps
other tumor antigens kill tumor cells.
Play a role in virus induce malignancy
• Natural Killer (NK) cells - can
attack tumor cells directly without
antibody coating or by Antibody
Dependent Cell Cytotoxicity (ADCC)
utilizing the Fc receptor on the NK
cells.
Mechanisms of Immunity
to Tumors
• Killer Macrophages - activated
by IFN-g elaborated by Helper T
lymphocytes. Participate in
ADCC and can lyse tumor cells
through release of TNF-a.
Immune surveillance:
• a constant monitoring process
aimed at eliminating emerging
cancers
recognition and
destruction of non-self
tumor cells .
Evidence for Immune Response
to Tumors
1) Infiltrate of lymphocytes and macrophages
associated with better prognosis in many
tumors.
2) Peripheral blood NK activity correlates with
survival.
3) Peripheral blood lymphocytes counts fall as
cancer overwhelms host; patients develop
anergy to skin tests.
Evidence for Immune Response
to Tumors
4) Non-specific vaccines can
stimulate macrophages and
improve prognosis. IFN-g and IL2 can stimulate NK cells and
improve outcome.
5) High incidence of some tumors
in immunosuppressed
individuals.
6) Spontaneous regression in some
tumors.
Immunosurveillance
Sporadic cancers occur in
immune competent people
HOW ???
Escape mechanisms :
• Growth of antigen-negative
variants.
• HLA underexpression .
• No expression of costimulatory
molecule .
• Immunosuppression .
Clinical
Features Of
Neoplasia
Clinical Features Of
Neoplasia
• Effects of Tumor On Host
• Grading & Clinical Staging Of
Cancer
• The Laboratory Diagnosis of
Cancer
Effects of Tumor On Host
• Tumor Impingement on nearby structures
– Pituitary adenoma on normal gland---compression of normal tissue ----Hypopitutrism
– Pancreatic carcinoma on bile duct-----Produce fatal billiary tract
obstruction
– Renal artery leiomyoma-------ischemia & hypertention
– Hormones production-----B cell tumor produce hyperinsulinism
– Ulceration/bleeding
– Colon, Gastric, and Renal cell carcinomas
• Infection (often due to obstruction)
– Pulmonary infections due to blocked bronchi (lung carcinoma),
Urinary infections due to blocked ureters (cervical carcinoma)
• Rupture or Infarction
– Ovarian, Hepatocellular, and Adrenal cortical carcinomas; Melanocarcinoma metastases
Effects of tumor on host
• Cancer Cachexia
• Paraneoplastic Syndromes
– Endocrinopathies
– Neuromyopathies
– Osteochondral Disorders
– Vascular Phenomena
– Fever
– Nephrotic Syndrome
Cancer Cachexia
• Progressive weakness, loss of
appetite, anemia and profound weight
loss (>20 lbs.)
• Often correlates with tumor size and
extent of metastases
• Etiology includes a generalized
increase in metabolism and central
effects of tumor on hypothalamus
• Probably related to macrophage
production of TNF-a
PARANEOPLASTIC SYNDROMES
Symptom complexes other than cachexia
that appear in patients with cancer and
cannot be readily explained either by the
local or distal spread of the tumor or by
the elaboration of hormones indigenous to
the tissue of origin of the tumor .
Occur in 10-15% of tumors
Paraneoplastic Syndromes
• Cushing’s Syndrome
– Small cell undifferentiated lung cancer
(ACTH) like product.
• Nonbacterial thrombotic Endocarditis
• Hypercoagulability
Paraneoplastic Syndromes
• Hypercalcemia (Cancer is the most common cause of
hypercalcemia by either humoral or metastatic
mechanisms)
– Squamous cell carcinoma of lung (PTH-like peptide)
– Renal cell carcinoma (prostaglandins)
– Parathyroid carcinoma (PTH)
– Multiple myeloma and T-cell lymphoma (IL-1 and
perhaps TNF-a)
– Breast carcinoma, usually by bone metastasis
Paraneoplastic Syndromes
• Hypoglycemia - caused by tumor over-production of
insulin or insulin like activities
– Fibrosarcoma, Cerebellar hemangioma,
Hepatocarcinoma
• Carcinoid syndrome - Caused by serotonin,
bradykinin or ?histamine produced by the tumor
– Bronchial carcinoids, Pancreatic carcinoma, Carcinoid
tumors of the bowel
Paraneoplastic Syndromes
• Polycythemia - caused by tumor production of
erythropoietin's
– Renal cell carcinoma, Cerebellar hemangioma,
Hepatocarcinoma
• WDHA syndrome (watery diarrhea, hypokalemia,
and achlorhydria) - caused by tumor production of
vasoactive intestinal polypeptide (VIP).
– Islet cell tumors, Intestinal carcinoid tumors
Paraneoplastic Syndromes
Neuromyopathies
• Myasthenia Gravis- A block in
neuromuscular transmission
possibly caused by host antibodies
against the tumor cells that cross
react with neuronal cells or perhaps
caused by toxins.
– Bronchogenic carcinoma, Breast
cancer
• Carcinomatous Myopathy probably immune-mediated
Paraneoplastic Syndromes
Osteochondral Disorders
• Hypertrophic Osteoarthropy clubbing, periosteal new bone, and
arthritis
– Isolated clubbing occurs in chronic
obstructive pulmonary disease and in
cyanotic congenital heart disease, but
the full-blown syndrome is limited to
lung cancer.
Paraneoplastic Syndromes
Vascular Phenomena
• Altered Coagulability - caused by the
release of tumor products
– Migratory Venous Thromboses
(Trousseau’s sign) Pancreatic, gastric,
colon, and bronchogenic carcinomas;
particularly adenocarcinoma of the lung.
– Marantic endocarditis - Small
thrombotic vegetations on mitral or aortic
valves that occur with advanced
carcinomas.
Paraneoplastic Syndromes
Fever
• Associated with bacterial infections
– Common where blockage of drainage
occurs
– Decreased immunity may play a role
• Not associated with infection
– Episodic as in Bar-Epstein fever with
Hodgkin's lymphoma; poor prognostic seen
in sarcomas, indicates dissemination
– Likely caused by response to necrotic
tumor cells and/or immune response to
necrotic tumor proteins.
Paraneoplastic Syndromes
Nephrotic Syndrome
• Excessive loss of protein in the
urine
– probably caused by damage to renal
glomeruli by tumor antigen-antibody
complexes.
Grading And Staging
• Grading is based on the microscopic
features of the cells which compose a
tumor and is specific for the tumor type.
• Staging is based on clinical,
radiological, and surgical criteria, such
as, tumor size, involvement of regional
lymph nodes, and presence of
metastases. Staging usually has
prognostic value.
Grading
• Estimate of aggressiveness of tumor
or level of malignancy based on
-cytological differentiation
-number of mitosis
Tumors are classified as grad 1,2,3,4
in order of increasing anaplasia
Staging
and
Grading
Gradin–
g the diagram below utilizing an adenocarcinoma as an
In
example, the principles of grading are illustrated:
Staging
• Anatomical spread of tumor based on
-size of tumor
-spread to regional L.N
-presence or absence of
metastasis
TNM staging system & AJC
Staging and Grading
• In this diagram
utilizing a lung
carcinoma as
an example, the
principles of
staging are
illustrated:
Diagnostic Methods for
Neoplasia
• History and Physical Examination
• learning from :
• talking to the patient .
direct examination
clues to the presence of a neoplasm.
Signs and symptoms such as weight loss,
fatigue, and pain may be present. A mass
may be palpable or visible.
Diagnostic Methods for
Neoplasia
• Radiographic Techniques
The use of plain
films (x-rays), computed tomography (CT),
magnetic resonance imaging (MRI),
mammography, and ultrasonography (US) may
be very helpful to detect the presence and
location of mass lesions. The findings from these
methods may aid in staging and determination of
therapy.
biochemical assays
• tumor markers: sometimes diagnostic or
prognostic
• can be helpful in monitoring effectiveness of
therapy or in detecting relapses/recurrences
• Serum tumor markers: prostate specific
antigen,CEA ,β-HCG ,α-FETOPROTEIN...etc
)may help to determine the presence of specific
neoplasms . not perfect screening tools in a
general population.
Laboratory Diagnostic
Methods for Neoplasia
• Laboratory Analyses
• General findings ( anemia, enzyme abnormalities
(alkaline phosphatase,LDH), URIN (hematuria) ,stool
occult blood further workup.
• Detection of specific genes (such as BRCA-1 for breast
cancer) may suggest an increased risk for some
malignancies.
Pathological Diagnostic Procedures
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FNA (fine needle aspiration)
cytological smears
biopsy
frozen sections
Diagnostic Methods for
Neoplasia
• Cytology
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sample cells
simple
cost-effective
minimally invasive.
e.g : Pap smear for the
diagnosis of cervical
dysplasias and neoplasms.
• Cells exfoliated into body fluids
can be examined.
• Fine needle aspiration (FNA)
can be used also.
Pap smear with dysplasia
cytology smear:
adenocarcinoma
Diagnostic Methods for
Neoplasia
• Tissue Biopsy and Surgery
Methods that
sample small pieces of tissue (biopsy) from a
particular site, often via endoscopic techniques
(such as colonoscopy, upper endoscopy, or
bronchoscopy) can often yield a specific
diagnosis of malignancy. At surgery, portions of
an organ or tissue can be sampled, or the
diseased tissue(s) removed and examined in
surgical pathology to determine the stage and
grade of the neoplasm.
frozen section
staining a frozen section
ancillary studies
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Imunohistochemistry
electron microscopy
cytogenetics
flow cytometry
cytokeratin stain on a carcinoma
AFP stain on a yolk sac tumor
EM: neurosecretory granules
EM: microvilli, tight junction in
an adenocarcinoma
Molecular studies
• PCR
• FISH
• Molecular profiling of tumor
Diagnostic Methods for
Neoplasia
• Autopsy
Sometimes neoplasms are not
detected or completely diagnosed during life.
The autopsy serves as a means of quality
assurance for clinical diagnostic methods, as a
way of confirming diagnoses helpful in
establishing risks for family members, as a
means for gathering statistics for decision
making about how to approach diagnosis and
treatment of neoplasms, and to provide material
for future research.