TUMOR IMMUNOLOGY
-
Mass of cell/tissue
Study of Ag associated w/ tumors
Immune response to tumor
Tumors effect on host immune system
Immune system to eradicate tumor
Nomenclature
1. Histologic cell type
2. Person who discovered
3. Appearance under the microscope
Malignant Tumor
Characteristics:
1. Increase in # of cells that accumulate
2. Invasion of tissues
3. Dissemination - tru lymphatic vessel or
blood
4. Metastasis
5. Characteristic nuclear cellular feature
6.
Receptor to integrin molecules → bind to
type IV collagen (w/c destroy the
extracellular matrix of collagen)
Stem Cell
1. Self Renewal
2. Capable of developing into multi lineage
3. Potential to proliferative
Note:
-
-
Normal process of
proliferation/development of stem cell, it
try to produce a daughter cell w/c try to
resemble the morphology of the parent
cell
Mutation: stem cell undergo some
abnormality as to its development,
production --- tumor is produced
Type of Tumor
➢ Benign
➢ Malignant
Benign Tumor
1. Encapsulated
cystic in nature
2. Grow slowly
3. Non spreading
4. Minimal Mitotic Activity
5. Resemble parent cell
-
“oma”
Except:
Lymphoma ]
Hepatoma ] malignant
Melanoma ]
Benign:
1. Adenoma - from gland (glandular
epithelial tissues)
2. Papilloma - from polyps
3. Non Neoplastic lesions
Hyperplastic tissues
overgrowth of the tissue that is
normally present in the organ
4. Normal tissue in foreign location
Pancreatic tissue in stomach
7.
8.
Secrete TNF alpha and TNF beta
promotes “Angiogenesis” or new
blood cell production
Recurrence
Chemotherapy
Irradiation
Surgery
Malignant:
1. Epithelial Origin
Squamous cell → lungs, esophagus
Transitional epith. → urinary bladder
Glandular epithelium → adenocarcinoma
2.
3.
4.
stomach, colon, pancreas
Adenocarcinoma
From glandular epithelium
(stomach, colon, pancreas)
Transitional Cell Carcinoma
Transitional epithelium in urinary
system
Amine precursor and decarboxylation
tumor
a. Neuroendocrine - from neural
crest and neural ectoderm
(small cell lung carcinoma)
b. Sarcoma - connective tissue
c. Teratoma - from germ layer
(meso, endo, ectoderm) of
ovaries and testes
Tissue
Prefix
1. Carcinoma
(Epithelial)
Glandular
Squamous
Adeno
Squamous
2. Sarcoma
(Connective)
Bone
Cartilage
Osteo
Chondro
3. Hematologic
(Blood components)
Lymphoid
Myeloid
Lympho
Myelo
2.
3.
4.
Cancer Stem Cell
1. Tumor initiating cell derived from
hematopoietic system
2. Capacity for self renewal
3. Develop to any cell type
4. Continued expansion of population of
malignant cells
Note:
It becomes a cancer cell once it is
exposed to carcinogens
5.
1st pregnancy >30 yrs old
Fibrocystic disease
Use of oral contraceptive
Ex. estrogen therapy
Prior breast wall/chest wall radiation
Causative Factors
Epidemiology
Leading Cause of Death
a. Lung
b. Colorectal
c. Breast
Increasing Cases
Lung, breast, pancreas, prostate, multiple
myeloma (MM), Hodgkin's lymphoma
Host Factor and Disease Associations
Decreasing Cases (development bc of vaccine)
Stomach, cervix, endometrium
Adult:
Male:
Female:
-
Prostate
Lung and Bronchus
Colorectal
Breast
Lung
Colorectal
Children:
1. ALL (acute lymphocytic leukemia)
2. Tumors of Central and Sympathetic
nervous system
3. Malignant lymphoma
4. Soft tissue sarcoma
5. Renal tumors
Risk Factors
1. Smoking
2. High fat, low fiber diet
3. Obesity
4. Sedentary lifestyle
5. Race
20% high in black than white
Americans
Predisposing Factor for Breast CA
1. Family history (esp 1 degree relative)
Environmental Factors
Aerosol and Industrial
Pollutants
Asbestos
Mesothelioma
Lead, copper, zinc, arsenic
Lung CA
Vinyl chloride
Liver
angiosarcoma
Benzene
Leukemia
Aniline Dyes
-
Drugs
Steroids
Hepatocellular
Stilbestrol
Vaginal
Adenocarcinoma
Estrogen
Endometrial
Hydantoin
Lymphoma
Chloramphenicol
Leukemia, lymphoma
Infectious Agents
1. Epstein Barr Virus
Burkitt’s lymphoma
Nasopharyngeal CA
2. Human papilloma ]
3. Herpes virus 2
] cervical CA
4. HIV/HTLV 3
Kaposi’s sarcoma
Non Hodgkins
5. HTLV 1
Non Hodgkins
6. Hepa B
Hepatocellular CA
Note:
-
Exposure to sunlight may result to
development of Thyminedimer (skin
cancer)
A-T
G-C
May mutation bc of sunlight
Disease Association
● Down Syndrome: leukemia
● Paget’s Disease: osteogenic sarcoma
● Cyrtopodium : testicular
● Neurofibromatosis: brain tumors
● Cirrhosis: hepatoma
● Achlorhydria, Pernicious Anemia (PA): gastric
CA
● Cholelithiasis: gallbladder
● Chronic inflammatory Bound diseases: colon
● Myasthenia Gravis: thymoma ]
● Pure T cell Aplasia: thymoma ] defective
thymus production
Stages of Carcinogenesis
1. Initiation
Irreversible mutation of
protooncogenes (pre-cancerous
gene)
2. Promotion
3.
Growth Enhancement (mutation
is being passed from one cell to
another)
Progression
Development of heterogeneity
(more heterogenous = more it is
not recognized by the immune
system)
Treatment susceptibility
Progression of Cancer
Involved precancerous conditions which progress
to series of cell alteration to become cancer:
1. Cervical CA
-
Squamous cell metaplasia →
squamous cell dysplasia → CA
in situ → invasive CA
2.
Endometrial CA
-
Endometrial hypoplasia →
atypical endometrial hyperplasia
→ CA in situ → invasive CA
Features:
1. Mutation and overexpression of
oncogenes
Resp for the growth and
proliferation of cancer cells
2. Deletion of tumor suppressor gene
Ex. P53 gene
Rb gene
tumor suppressor gene: genes
that helps the body to fight the
cancer cells
Cancer Predisposing Genes
1. Affects rate of exogenous conversion of
pre-carcinogens to actively carcinogenic
form
2. Affects host ability to repair damage DNA
3. Alter ability recognize and eradicate
tumors
4. Affects apparatus that regulate normal
cell growth and proliferation
Protooncogenes
Regulates growth and differentiation
Requires growth and transcription factors
Pre-cancerous gene; acted upon by
carcinogens
Oncogenes
target of carcinogens
a.
b.
c.
d.
e.
f.
cancer-inducing genes
Family:
Growth Factor - sis oncogene
EGFR (epidermal growth factor receptor)
Membrane Associate PK (sac oncogene)
PK: protein=kinase
Membrane related guanine triphosphate
protein (ras oncogene)
Cytoplasmic PK (ras oncogene)
Transcription regulator located in nucleus
(c-myc oncogene)
Oncogenes and Associated Diseases
● ab1: CML (chronic myelogenous leukemia)
● myc: Burkitt’s lymphoma
● N-myc: Neuroblastoma
● EGFR, HER2: mammary CA
- EGFR: epidermal growth factor receptor
- HER2: human epidermal growth factor
● Ras: Wide variety of tumors
Body Defenses Against Cancer
1. Tumor express Ag and recognized as foreign
2. Normal response fails to prevent growth of
tumors
3. Immune system can be stimulated to kill
tumor and get rid of the host tumor
Effectors of Tumor Eradication
1. T lymphocyte
2.
3.
4.
Lack of MHC expression
- MHC: major histocompatibility complex
are needed by C cytotoxic cells
Px is immunodeficiency
Immunoediting
- the tumor already mutated several times
wherein body can no longer remove it
● Elimination phase: tumor too aggressive
● Equilibrium phase: mutation occur
overtime
● Escape phase: tumors mutated beyond
the control of immune system
Cancer Staging
Cancer divided into groups
Treatment is highly dependent on the
stage
A. The process by which cancer is divided into
groups of early and late disease
B. Useful for prognosis and guiding therapy
C. Mutations
Activation of growth factors and
oncogenes
Inhibition of apoptosis, tumor suppressor
Inhibition of cell cycle regulation genes
Stage I: localized primary tumor (in situ)
Stage II: invasion of tumor tru blood vessel
Stage III: migration to regional lymph nodes
Stage IV: metastasis and invasion to distant tissue
CTL → in association of MHC II
2.
3.
4.
(cytotoxic T lymph)
*CTT- provides effective antitumor activity
in vivo
NK - ADCC (Ab dependent cell mediated
cytotoxicity)
*NK-activated through direct recognition
of tumors as a consequence of cytokine
produced by tumor specific T lymphocyte
*play a role in immunosurveillance
Macrophages - produced TNF w/c can kill
tumors
Ab → produced against tumor Ag w/c serves
as a tumor marker
Mechanism of Escape of Tumors
Severity depends on:
1. Tumor size
2. Histology
3. Regional lymph node involvement
4. Metastasis
Pathology of Tumors:
● Poorly Differentiated - similar to fetal
tissues or embryonic tissues
→ more aggressive; poor prognosis
●
1.
Tumor Ag - poor immunogenic
- Body can recognize if it is foreign or not
Well Differentiated - similar to normal cell
TNM System
T - tumor size
N - lymph node involvement
M - detection of metastasis
Tumor Markers - Ag produced by tumors
Virally induced - more immunogenic
Chemically induced
Significance
1. Used to differentiate normal from tumor
infected
2. To screen cancer
3. Monitor recurrence
compare results with the previous
results
tumor markers do not recline
4. Must reveal tumor while in susceptible stage
5. Can be measured in body fluids by
biochemical, immunological or molecular test
-
Ex. EBV causes Burkitt lymphoma
Carcinofetal Ag
Expressed during fetal life (embryonic
life)
Depression of gene normally expressed
during fetal life
Spontaneous Ag
No known mechanism
Classifications of Tumor Markers
Ideal Tumor Markers
1. Result occur only in px w/ malignancy
2. Correlate w/ stage and severity
higher stage = more severe
3. Reproducible
allow comparison with previous
allow to monitor for treatment
response of px
1st tumor Marker Discovered: Bence Jones protein
for MM
Categories of Tumor Markers
1. TSA (tumor specific Ag)
2. TAA (tumor associated Ag)
3. Carcinofetal Ag
4. Spontaneous tumor Ag
TSA (Tumor Specific Ag)
1. Chemically induced
2. Uniquely associated w/ each tumor
3. Not found in normal cell
4. No cross reactivity bet. different tumors
TAA (Tumor Associated Ag)
1. Virally induced
2. Cell surfaced molecules produced by virus
produced by host
Not found in the virus itself but
produced by host immune system in
response to the infection caused by
the virus
3. Virus specific - regardless of body area
affected
Enzymes
PSA -- prostate
Oncofetal
AFP -- Hepatocellular
CEA -- Colorectal
Hormones
Beta hCG -- Trophoblastic,
medullary
Calcitonin -- thyroid
ACTH -- small cell lung
Mucins
CA 125, CA 17-9 -- ovary
CA 17-29, CA 15-3 -- breast
Immunoglobulin
Bence Jones -- MM
Genetic
Alteration
HDR2/Neu -- breast
Other Proteins
HE4 -- ovary
Tg -- thyroid
NMP22 -- bladder
-
BTA -- bladder
Complement Factor H
related protein -- bladder
*PSA: prostate specific Ag
*AFP: alpha fetoprotein
*CEA: carcino embryonic Ag
*Beta hCG: beta human chorionic gonadotropin
*ACTH: adrenocorticotropic hormone
*HER2/Neu: human epidermal
*HE4: human epididymis 4
*NMP22: nuclear matrix protein 22
*BTA: bladder tumor associated proteins
Methods for Screening
1. Colon - occult blood test
presence of occult blood = colon
cancer
colorectal cancer: stool occult,
blood test colonoscopy
2. Cervical CA - PAP’s smear
3. Breast - self exam, mammography
4. Testicular - digital rectal exam
Lab Test:
1. Gross and Microscopic tissue dissection
Biopsy
Gross dissection and
microscopic analysis
2. Tumor Marker (serological test)
Detection of Ag/tumor markers
3. Molecular Tests
DNA/RNA
Molecular Diagnostic test
1. Cytogenetic Studies
For detection of exact
chromosomal defects
Ex. karyotyping
2. Nucleic Acid Amplification Techniques
Detects mutations, deletions of
genes
Ex. PCR
3. FISH (Fluorescence in situ hybridization)
Uses nucleic acid probes that
binds w/ a specific target
sequence w/c identify the
position of defects
uses nucleic acid probes that is
capable of binding with target
sequences, tagged with
fluorophors (Fluorescent labels)
for identification
Non fluorescent labels are also
available (Enzymes and silver
stain)
Characteristics of Ideal Tumor Markers
1. Must be produced by tumor and must be
secreted into biological fluid to be
analyzed
2. Half life must be long enough to permit
increased in concentration
3. Must increase to significant levels while
the disease is still treatable with few false
negative
4. Antigen must be absent from population
without the malignant disease.
Frequently Requested Tumor Markers
● AFP (alpha fetoprotein)
Produced by liver up to 14 weeks
-
Increased > 14 weeks → neural tube
defects
-
-
Spina bifida
Anencephalopathy
gestation (peak values reached at 14
weeks of gestation) –
Inc. AFP (Maternal & AF) indicates
Neural Tube Defect (ex: Anencephaly
and spina bifida) – Used extensively in
the diagnosis of liver cancer –
Oncofetal antigen that is expressed in
some germ line tumors (teratoblastoma
and testicular or ovarian carcinomas)
●
Seminomatous tumor
directly from malignant germ
cells
● Nonseminomatous tumor
Differentiated to:
Embryonal carcinoma
Teratoma
Choriocarcinoma
Yolk sac tumor
Use of Serum AFP and hCG for Testicular Cancer
Classification
Germ cell
tumor
Yolk sac tumor
(non)
AFP
HCG
Increased
No
Seminomatous
●
●
●
No
(+)
CA 125
Ovarian cancer
Increased fallopian tube, endometrium,
endocervix cancer
The only clinically accepted serologic
marker of ovarian cancer
Expressed in the ovary (normally found in
the adult fallopian tube, endometrium and
endocervix)
Used for monitoring response and
possible recurrence in women
Used for predicting the success of
surgery and efficacy of therapy
CEA (Carcino Embryonic Ag)
Colorectal CA
Increased as well in: breast, lungs, ovary,
GIT
Oncofetal antigen – Most widely used
tumor marker for colorectal cancer
Also elevated in patients with
malignancies of the gastrointestinal tract,
lung, breast and ovary
It is used as a major monitoring
parameter for early detection of
recurrence or relapse after surgical
removal of tumor, and to monitor
response to radiation or chemotherapy.
Beta hCG
Produced by placenta during pregnancy
It is normally secreted during pregnancy
by syncytiotrophoblastic tissue of the
placenta to maintain the corpus luteum
during pregnancy.
It is also regularly secreted by
malignancies of female and males
Non Pregnant
Female: choriocarcinoma
trophoblastic tumor
hydatidiform mole (H-mole)
Male: testicular carcinoma
Gestational Trophoblastic disease
1. Hydatidiform mole
2. Gestational tropoblastic neoplasia
3. Choriocarcinoma
4. Placental site trophoblastic tumor
●
PSA (Prostate Specific Ag)
Prostate enlargement
-
Level of PSA is correlated with the size of
prostate gland
Nonspecific for prostate cancer
Produced by male prostate gland
Increased in prostate cancer
In healthy patient: level correlates with
gland size
Increased level is associated with:
Benign prostatic hypertrophy
Weakly aggressive cancer
Highly aggressive cancer
*PSA: Free to bound ratio- low or increasing rate
of 0.5ng/ml per year
Interpretation: associated with cancer
1.
2.
3.
4.
Enlarged:
Prostate inflammation
Prostate infection
Benign prostate hypertrophy
Recent ejaculation
Prostate Cancer:
Free: Brand Ratio
>0.5 ng/mL per year increase
Bound:
● Alpha 2 macroglobulin
● Alpha 1 antichymotrypsin
Screening test:
1. Digital rectal examination (DRE) of the
prostate gland
2. PSA
PSA is an enzyme synthesized
almost exclusively in the
prostate
US FDA and ACS recommend
screening of prostate cancer in
men over 50 years old and with
younger male with high risk
Measured by
immunoassay
Forms:
1. Free
2. Complexed with a1 antichymotrypsin (AACT)
3. Complexed with a2 macroglobulin (AMG)
Immunotherapy (Treatment)
1. Passive
Administration of Ab or
cytokines
involves the passive transfer of
antibody, cytokines or cells to
patients
Barriers:
1. Possible recipient rejection
2. GVHD
3. Fragility of host cell
Examples:
a. Allogenic T cell
Transfer:
Graft versus
leukemia
Adoptive T
cell therapy
b. Autologous T cell-TIL
(Tumor Infiltrating
Lymphocyte) harvested
and expanded in vito
through IL-2
2.
Active (up to the immune system to
produce Ab)
patient is treated in a manner to
stimulate them to mount immune
response against the tumor
Example:
a. Adjuvants
BCG - for superficial
bladder cancer
b. Stimulatory cytokines
TNF-α, IFN-y, IL-1, IL2)
c. Cancer vaccines
Ag is given
when cancer is
associated virus,
vaccine is directed
with appropriate
epitope