tumor immunity
DESCRIPTION
TRANSCRIPT
Dr. Aye Aye Tun
Lecturer
Pathology Unit
Aimst University
Explain how the immune system of the
host responds to the presence of a
tumour
Learning objectives:
This lecture provides an
understanding of
Tumor antigens
Antitumor effector mechanism
Immunosurveillance
Learning outcomes
At the end of this lecture student will be able to
Prove the role of immunity in cancers
List tumor antigens and specify their importance
Describe the Immunosurveillance of cancer
Explain how the immune system of the host responds to the presence of a tumour
Explain the mechanisms by which tumors evade the immune system
Tumors arise from accumulated
genetic mutations
Carcinogenesis is a multistep process at
both the phenotypic and the genetic
levels
resulting from the accumulation of
multiple mutations
Nonlethal genetic damage lies at the
heart of carcinogenesis
A tumor is formed by the clonal
expansion of a single precursor cell
that has incurred genetic damage
(i.e., tumors are monoclonal)
Types of genes that control cancer
Four classes of regulatory genes
1. growth-promoting proto-oncogenes
2. growth-inhibiting tumor suppressor
genes
3. genes that regulate programmed cell
death (apoptosis)
4. genes involved in DNA repair
principal targets of genetic damage
The immune system play a
critical role in distinguishing self from nonself
molecules
Eliminating infectious agents
Immune system react to
antigens that it recognizes
as foreign
Tumor cells can be recognized by
the immune system as non-self
Paul Ehrlich proposed that
immune-mediated recognition of
autologous tumor cells can be
capable of eliminating
transformed cells
Immune surveillance Lewis Thomas and Macfarlane Burnet
Recognition and destruction of
non-self tumor cells by the
immune system
(immunological resistance of the host
against the development of cancer)
regression of metastases after removal of primary tumor
infiltrations of tumors by lymphocytes and macrophages
lymphocyte proliferation in draining sites of cancer
direct demonstration of tumor-specific T cells and antibodies in patients
increased cancer risk after immunosuppression and immunodeficiency
Evidence for tumor immunity
Cancer immunoediting describe
the effects of the immune
system in preventing tumor formation
in “sculpting” the immunogenic
properties of tumors to select tumor
cells that escape immune elimination
How does the immune system eliminate
cancer cells?
How do cancer cells escape from
Immunosurveilance?
How can we help to win the battle
between immune system and cancers?
Many tumors do elicit an immune
response due to tumor antigens
Many tumors evade host immune
response through several
mechanisms
two categories
based on their patterns of expression
Tumor-specific antigens - present only
on tumor cells and not on any normal cells
Tumor-associated antigens - present on
tumor cells and also on some normal cells
Classification of tumor antigens
Classification of tumor antigens
based on their molecular structure and source
1. Products of Mutated Oncogenes and Tumor Suppressor Genes
2. Products of other Mutated Genes
3. Over expressed or Aberrantly Expressed Cellular Proteins
4. Tumor Antigens Produced by Oncogenic Viruses
5. Oncofetal antigens
6. Altered glycolipids and glycoproteins
7. Cell type-specific differentiation antigens
TUMOR ANTIGENS
Products of mutated genesderived from the products of mutant proto-
oncogenes, tumor suppressor genes, or other mutated genes
synthesized in the cytoplasm of tumor cells, and like any cytoplasmic protein, they may enter the class I MHC antigenprocessing pathway and be recognized by CD8+ T cells
In addition, these proteins may enter the class II antigen-processing pathway in antigen-presenting cells that have phagocytosed dead tumor cells, and thus be recognized by CD4+ T cells also
TUMOR ANTIGENS
Products of mutated
genesproducts of β-catenin, RAS, p53,
and CDK4 genes BCR-ABL proteinBecause the mutant proteins are present
only in tumors, their peptides are
expressed only in tumor cells
TUMOR ANTIGENS
Overexpressed or aberrantly
expressed proteins
Tumor antigens may be normal cellular
proteins that are abnormally expressed
in tumor cells and elicit immune
responses
Tyrosinase , MAGE(melanoma antigen gene )
is expressed on melanomas
TUMOR ANTIGENS
Oncofetal antigens
proteins that are expressed at high levels on cancer cells and in normal developing (fetal) but not adult tissues
their main importance is that they provide markers that aid in tumor diagnosis
TUMOR ANTIGENS
Oncofetal antigensCarcino-embryonic antigens (CEA)Carcino-embryonic antigens (CEA)
- - Normally expressed during fetal life on fetal gut
- GIT, pancreas, biliary system and cancer breast
Alpha fetoprotein(AFP):
- - Normally expressed in fetal life
- hepatocellularcarcinoma
TUMOR ANTIGENS
antigens produced by oncogenic
viruses
Oncogenic viruses (eg; HPV,EBV, HBV)
produce proteins that are
recognized as foreign by the
immune system
TUMOR ANTIGENS
Altered Cell Surface Glycolipids and Glycoproteins
Expression of higher than normal levels and/or abnormal forms of surface glycoproteins and glycolipids
diagnostic markers and targets for therapy
These altered molecules include gangliosides, blood group antigens, and mucins
TUMOR ANTIGENS
Altered Cell Surface Glycolipids and Glycoproteins
These include
CA-125 - expressed on ovarian carcinomas
CA-19-9- expressed on carcinoma in pancreas & biliary tract
MUC-1 - expressed on breast carcinomas
TUMOR ANTIGENS
Cell Type-Specific Differentiation Antigens
Tumors express molecules that are normally present on the cells of origin
Important for identifying the tissue of origin of tumors
These antigens are called differentiation antigens because they are specific for particular lineages or differentiation stages of various cell types
TUMOR ANTIGENS
Altered Cell Surface Glycolipids and Glycoproteins
Mucins are high-molecular-weight glycoproteins containing numerous O-linked carbohydrate side chains on a core polypeptide
Tumors often have dysregulated expression of the enzymes that synthesize these carbohydrate side chains, which leads to the appearance of tumor-specific epitopes on the carbohydrate side chains or on the abnormally exposed polypeptide core
TUMOR ANTIGENS
Altered Cell Surface Glycolipids and Glycoproteins
These include
CA-125 - expressed on ovarian carcinomas
CA-19-9- expressed on carcinoma in pancreas & biliary tract
MUC-1 - expressed on breast carcinomas
TUMOR ANTIGENS
Cell Type-Specific Differentiation Antigens
typically normal self-antigens, and therefore they do not induce immune responses in tumor-bearing hosts
For example, lymphomas may be diagnosed as B-cell-derived tumors by the detection of surface markers characteristic of this lineage, such as CD10 and CD20
TUMOR ANTIGENS
TUMOR ANTIGENS
Host Response to Tumors
Cellular Immunity
CTL (Cytotoxic T-lymphoctyes)
NK cells
Macrophages
Humoral Immunity
Antibody production by the host against host tumor cells or their constituents for tumor antigens
Host Response to Tumors
CTL (Cytotoxic T-lymphoctyes)CTLs are the major immune defense
mechanism against tumors
CTLs recognize peptides derived from cytoplasmic proteins that are displayed bound to class I major histocompatibility complex (MHC) molecules
CTLs play a protective role against virus-associated neoplasms (e.g., EBV- and HPV-induced tumors)
Host Response to Tumors
NK cellsare capable of destroying tumor cells
without prior sensitization – 1st line defense against tumor cells
After activation with IL-2 and IL-15, NK cells can lyse a wide range of human tumors
recognize stress-induced antigens that are expressed on tumor cells and cells that have incurred DNA damage and are at risk for neoplastic transformation
Host Response to Tumors
MacrophagesActivated macrophages exhibit
cytotoxicity against tumor cells in vitro
Activated macrophages may kill tumors by mechanisms similar to those used to kill microbes
(e.g., production of reactive oxygen metabolites or by secretion of TNF)
Host Response to Tumors
T cells, NK cells, and
macrophages may collaborate
in antitumor reactivity
interferon-γ, a cytokine
secreted by T cells and NK
cells, is a potent activator of
macrophages
Host immune response evasion by tumor cells
Selective outgrowth of antigen-negative
variants
loss or reduced expression of
histocompatibility antigensLack of costimulation ImmunosuppressionAntigen maskingApoptosis of cytotoxic T cells
Host immune response evasion by tumor cells
Selective outgrowth of antigen-negative
variants
- during tumor progression, strongly immunogenic
subclones may be eliminated loss or reduced expression of
histocompatibility antigens
- tumor cells may fail to express normal levels of HLA
class I molecules, thereby escaping attack by
cytotoxic T cells Such cells, however, may trigger NK
cells
Host immune response evasion by tumor cells
Lack of costimulation - sensitization of T cells requires two
signals, one by a foreign peptide
presented by MHC molecules and the
other by costimulatory molecules
- although tumor cells may express
peptide antigens with class I molecules,
they often do not express costimulatory
molecules
Host immune response evasion by tumor cells
Immunosuppression-Many oncogenic agents (e.g., chemicals
and ionizing radiation) suppress host
immune responses-Tumors or tumor products also may be
immunosuppressive. For example, TGF-β,
secreted in large quantities by many
tumors, is a potent immunosuppressant
Host immune response evasion by tumor cells
Antigen masking-The cell surface antigens of tumors may be
hidden, or masked, from the immune system by
glycocalyx molecules, such as sialic acid–containing
mucopolysaccharides
Apoptosis of cytotoxic T cellsSome melanomas and hepatocellular carcinomas
express FasL. It has been postulated that these
tumors kill Fas-expressing T lymphocytes that
come in contact with them, thus eliminating tumor-
specific T cells
Immunodiagnosis
Tumor antigens useful as tumor markers
released only from tumor tissue
Specific for a given tumor type
Has direct relationship to the tumor cell
Present in all patients with tumor
Tumors release antigen macromolecules that can be detected in vivo and in vitro
Immunodiagnosis
Examples of tumor antigens used for tumor markers
Alpha-Fetoprotein
Beta-subunit of human chorionic gonadotropin (B-HCG)
Prostate-specific antigen (PSA)
CA 125
Radio-labeled monoclonal antibody B72.3
Carcinoembryonic Antigen (CEA)
Immunodiagnosis
Immunohistochemistry Categorization of undifferentiated
malignant tumors
Determination of site of origin of
metastatic tumors
Detection of molecules that have
prognostic or therapeutic significance
Immunotherapy
Adoptive T cell therapy (AIT)
Passive immunotherapy using antibodies
Active-specific immunotherapy by using
vaccines
Passive immunotherapy: mAbs
Herceptin: anti-HER-2/neu in breast cancer patients
Rituximab: anti-CD20 in patients with non-Hodgkin’s lymphoma
Limitations: clearance by soluble Ags, antigenic variation of the tumor, inefficient killing or penetration into the tumor mass