Download Tumor Immunology

Tumor Immunology
Lymphocyte
Tumor cell
Priya Weerasinghe MD. PhD.
Department of Pathology and
Laboratory Medicine
UT Medical School - Houston
Texas
Tumor Immunology
Objectives:
To study the generation of immune responses to tumor cells
Tumor Antigens / Tumor Specific Transplantation Antigens
(TSTAs)
Categories of Tumor Antigens
Carcinogen-induced Tumors
Tumor antigens encoded by oncogenes
Immunologic factors that influence the incidence of
cancer
Effective mechanisms in tumor immunity
B cell responses to tumor
Cell mediated responses to tumor
Limitations in effectiveness of immune responses against tumors
Immunodiagnosis
Tumor immunoprophylaxis
Immunotherapy
How does immune responses against
tumor cells occur?
The expression of cell surface molecules give rise to
tumor antigens on the surface of the tumor cell.
Experiments on mice showed that when tumor cells were
injected to syngeneic (MHC restricted) mice, cells formed
nodules that grew for few days and then regressed.
When the identical tumor cells were reinjected –tumor
cells did not grow. i.e. these mice had generated an
immune response towards the tumor cells.
What are tumor antigens/tumor
specific transplantation antigens
(TSTAs)?
Immunogenic tumor antigens:
Immunogenic tumor antigens, similar to a
response to foreign antigens, generates
stimulation of effector mechanisms
Non immunogenic tumor antigens:
The self antigens that show some degree of
immune tolerance.
Tumor antigens (cont…)
Some tumor antigens consist of molecules that are
unique to the tumor cell but not to the normal cell.
Some tumor antigens are qualitatively not different from
those found on normal cells but are over expressed on
the tumor cell. Eg:
1. HER in some breast and ovarian cancers- over
expression of HER-2/neu-1 oncogene
2. ras oncogene on some human prostate cancer
cells
These commonly expressed tumor antigens can serve as
targets for immune based therapy. Eg:
1 monoclonal antibodies against HER to treat
breast and ovarian cancer.
Carcinogen-induced tumor antigens
Carcinogens can induce mutations in normal genes that were
silent.
These mutations can give rise to an array of different gene
products.
There is very little or no cross reactivity in these tumor antigens.
This lack of cross reactivity is due to the random mutations
induced by the chemical or physical carcinogen. Eg:
When methylcholanthrene is applied repeatedly to
genetically identical animals, tumors will develop. But
tumor antigens will be different and there will be no cross
reactivity. Same is true for physical carcinogens such as
UV light or x ray.
Categories of tumor antigens
Category
Normal
cellular
gene
products
Embryo
nic
Type of
Antigen
Name of Antigen
Types of Cancer
Oncofetal
antigens
MAGE-1
MAGE-2
CEA
Several
Several
Lung, pancreas, breast,
colon, stomach
Liver, melanoma, carcinoma
of bladder, lung, testis
AFP
Differe
ntiation
Normal
intracellular
enzymes
Oncoprotein
Carbohydrate
Prostate specific
antigen, CT antigen
tyrosinase
HER-2/neu
Lewis
Prostate
Melanoma
Breast, ovary
Lymphoma
Clonal
amplifi
cation
Ig isotype
Specific antibody of
B cell clone
Lymphoma
Mutant
cellular
gene
products
Point
mutatio
ns
Oncogene
product
Suppressor
gene product
CDK
Mutant RAS protein
Mutant P53
Several
Viral gene
products
Transfo
rming
viral
gene
Nuclear protein
E6 and E7 proteins of
HPV
Mutant CDK-4
Several
Melanoma
Cervical
Activation of cellular proto-oncogenes in
human cancer
Proto-oncogene
Activation
mechanism
Chromosomal
change
Associated
cancer
C-myc
Genetic
rearrangement
Translocation: 814. 8-2 or 8-22
Burkitt’s
lymphoma
C-abl
Genetic
rearrangement
Translocation 922
CML
C-H-ras
Point mutation
Bladder
carcinoma
C-K-ras
Point mutation
Lung and colon
carcinoma
N-myc
Gene amplification
Neuroblastoma
Immuno surveillance
Immunologic resistance against the development of cancer
or the ability of innate and adoptive immuno-responses that
seek and destroy tumor cells.
-Experimental studies of immunocompromised animals
-Epidemiological studies of patients with various
immunodeficiencies
(primary, secondary or acquired)
Immunologic resistance against the
development of cancer
APC
T helper cell
CD4
CD3
T helper cell
CD4
1)
The cells (CD4+) must
recognize antigen presented by MHC
class II molecules on an APC (antigen
presenting cell) (dendritic cell or
macrophage).
Activated Th1 cell secretes IL-2
and IFN-, which activates CTLs.
CD3
IFN‐
IL‐2
CD8
2)
CD3
Tumor cell
Activated CTL
Activation of CTL + NK cells
+ macrophages
Effector mechanisms in tumor immunity
Dr. Andrejs Liepins/ Science Photo Library
“Kiss of Death”
Effector cells in tumor immunity
CTLs – antigen specific and MHC restricted.
CTLs express CD8.
CTLs kill their targets by using Perforin, Granzymes, Cytokines
(TNF-β, IFN-)
Fas and Fas ligand.
NK cells are morphologically large granular lymphocytes (LGLs).
Non-T and non-B lymphocytes lack surface CD3, CD4, CD8 and CD19. They
do not express immunoglobulins or TCRs.
NK cells express CD16 and CD56.
NK cells kill by releasing perforin, granzymes and cytokines (IFN- and
TNF).
Reaction- nonspecific (they do not use a T cell receptor).
Lymphokine activated killer cells (LAK cells) are morphologically LGLs.
Non-T non-B lymphocytes.
Reaction– nonspecific.
NK-ADCC- NK cells are the major cell type that carries out
antibody-dependent cellular cytoxicity (ADCC).
NK cells have Fc receptors (CD16) that recognize Fc portion of IgG.
Effector mechanisms in tumor immunity
Effector Mechanism
Comment
B cells and antibodies (ADCC, CDC)
Role in immunity– poorly
understood
T cells (cytolysis, apoptosis)
Virally- and chemically–induced
tumors
NK cells (cytolysis, apoptosis,
ADCC)
Tumor cells not expressing MHC
class 1 alleles- rejected by NK cells
LAK cells (cytolysis, apoptosis)
Anti tumor response- to adoptive
transfer to LAK cells
Macrophages and neutrophils
Activated– by using bacterial
products
Cytokines (apoptosis, recruitment
of inflammatory cells)
Using adoptively transferred tumor
cells- eg: GM-CSF
Limitations of effectiveness of immune
responses against tumors
Tumor Related Mechanisms
of Escape
Host Related Mechanisms of
Escape
Failure of tumor to provide a
suitable antigenic target or an
effective immune response;
- lack of tumor antigen
- lack of MHC class 1
-deficient antigen processing
-antigen modulation
-antigenic masking of tumor
-resistance of tumor to
tumoricidal pathways
-lack of co-stimulatory signals
-production of inhibitory cytokines
-shedding of tumor antigens
Failure of host to antigenic tumor
cells:
-immuno-supression or
immunodeficiency
-deficiency in inducing
apoptosis and cell death
signaling
- infections or old age
- deficiency in tumor antigen
presentation by host APC
- failure of host effector
cells to reach the tumor
(eg: stromal barrier)
- failure of host to kill
variant tumor cells
- T reg hindrance to tumor
immunity
Immuno-diagnosis
1. Immunohistochemistry-
Antibodies to specific antigens detected by amplified
signals.
Applications: Diagnosis on surgical specimens.
to identify the original cancer
to classify the type of cancer
to predict the aggressiveness of the tumor
2. Morphoproteomics-
-Combination of disciplines of histopathology, molecular
biological and computational biology.
-Customizing therapy for individual patients.
Tumor immuno-prophylaxis
Cervical cancer vaccine:
-Gardasil (by Merck Pharmaceuticals) –
Prevents human papilloma virus (HPV )16, 18, 6, 11.
-Cervarix: (by GlaxoSmithKline)
Prevents HPV 16 and 18
Tumor immuno-therapy
-Stimulate the immune system, reject and destroy tumors.
-BCG immunotherapy for early stage bladder cancer.
-Imiquimod: topical immunotherapy
Immuno-therapy
Name
Trade name
Used to treat
Target
Year approved
Rituximab
Rituxan
Non‐Hodgkin’s lymphoma
CD20
1997
Trastuzumab
Herceptin
Breast cancer
Erb b2
1998
Gemtuzumab ozogamicin
Mylotarg
Acute myelogenous leukemia (AML)
CD33
2000
Alemtuzumab
Campath
Chronic lymphocytic leukemia CD52
(CLL)
2001
Ibritumomab tiuxetan
Zevalin
Non‐Hodgkin’s lymphoma
CD20
2002
Panitumumab
Vectibix
Colorectal cancer
EGFR
2006
Cetuximab
Erbitux
Colorectal cancer, Head and neck cancers
EGFR
2004 Bevacizumab
Avastin
Colorectal cancer
VEGF
2004
USMLE Questions
1. In antigen recognition by cytolytic T lymphocytes (CTLs), T cell receptor
recognizes antigen bound to
a. class I antigens
b. Class 11 antigens
c. Class 111 antigens
d. C3b
e. Fc
2. The most important factor related to the prognosis of breast cancer is
a. The presence of activated oncogenes
b. The histological type and grade
c. The size of the tumor
d. The status of axillary lymph nodes
e. The presence of estrogen receptors
3. Oncogene activation has been implicated in the development of all these
malignancies EXCEPT
a. Carcinoma of the urinary bladder
b. Neuroblastoma
c. Chronic myelocytic leukemia
d. Burkitt’s lymphoma
e. Retinoblastoma