Embed Size (px)
Citation preview
CANCER
IMMUNOLOGY
Presented by: Zahabiya Dhankot
(M.Sc. Biochemistry)
TOPICS INCLUDED
The cancers of the immune system.
How the tumor growth is enhanced in the body
Tumor antigens
Induction of immune response and participation of
various cells
Elimination of tumor and cancerous cells.
Cancer immunotherapy
INTRODUCTION
In the body the number of cells is maintained after
maturation by creating a balance between the
number of cells proliferated and the cells
undergoing death. If this control mechanism is
disturbed within the body then uncontrolled cell
multiplication occurs which leads to the tumorous
or cancerous growth.
Immune system is the defense mechanism of the
body against any foreign particles.
TUMORS OF IMMUNE SYSTEM
Lymphoma proliferate as solid tumors within alymphoid tissue such as bone marrow, lymph nodesand thymus.
Leukemia can develop as single cell and aredetected by increase in cell number in blood andlymph.
It can be developed in myeloid or lymphoidlineages.
Historically, it is classified on the basis of clinicalprogression of disease.
They are
Acute leukemia
They appear suddenly and rapidly progress
They have good prognosis and permanent
remission can often be achieved.
Tend to arise in less mature cells.
It includes Acute Lymphocytic Leukemia(ALL)
and Acute Myelogenous Leukemia(AML).
Chronic leukemia
They are less aggressive and develop slowly and
mild, barely symptomatic disease.
They arise in mature cells.
These includes chronic lymphocytic
leukemia(CLL) and chronic myelogenic
leukaemia(CML).
They are found mostly in adults.
ENHANCEMENT OF TUMORS
BY ANTITUMOR ANTIBODIES
The immunization of the tumor itself sometimesdid not protect against tumor growth, but actuallyenhance the growth of tumor.
Here the antitumor antibodies itself act as ablocking factor.
BY ANTIGENIC MODULATION
Certain tumor specific antigens are observed todisappear from the surface of tumor cells in thepresence of serum antibody and then to reappear
after the antibody is no longer present. Thisphenomenon is called antigenic modulation.
POOR EXPRESSION OF CLASS-I MHCMOLECULES
CD8+ CTLs recognize antigens only associatedwith class-I MHC molecules.
Any changes in expression of class-I MHCmolecules will decrease the CTL mediated immuneresponse.
Many tumors shows decrease level of class- I MHCmolecules.
The decrease in its expression is often accompanied
by progressive tumor growth and so the absence of
MHC molecule on tumor cell is generally
indication of poor prognosis.
REQUIREMENT OF STIMULATORY AND
COSTIMULATORY SIGNALS
Activation signal:- It is triggered by recognition of
a peptide MHC molecule complex by the T-cell
receptor.
Co-stimulatory signal:- It is triggered by the
interaction of B7 on antigen presenting cells with
CD28 on the T-cells.
Both these signals are needed to induce IL-2
production and proliferation of T-cells.
TUMOR ANTIGENS
Two types of antigens have been identified on
tumor cells:
1) Tumor Specific Transplantation Antigen(TSTA)
2) Tumor Associated Transplantation Antigen(TATA)
TSTA are unique to tumor cells and do not occur on
normal cells in the body.
These are presented with class-I MHC molecules,
including a cell mediated response by tumor
specific CTLs.
TATA are unique to tumor cells, they may be a
proteins that are expressed on normal cells during
fetal development when the immune system is
immature and unable to respond.
Reactivation of the embryonic genes that encode
these proteins in tumor cells result in their
expression of the fully differentiated tumor cells.
It is now clear that the tumor antigens recognize by
human T cells fall into four major categories:
1) Antigens encoded by genes exclusively expressed
by tumors.
2) Antigens encoded by variant forms of normal
genes that have been altered by mutations.
3) Antigens normally expressed at certain stages of
differentiation or only by certain differentiation
lineages.
4) Antigens which are over expressed in particular
tumors.
Many tumor antigens are cellular proteins that give
rise to peptides presented with MHC molecules.
These antigens have been identified by their ability
to induce the proliferation of antigen specific CTLs
or helper T-cells.
INDUCTION OF IMMUNE
RESPONSE BY TUMORS
Tumor antigens can induce both humoral and cell-
mediated immune responses resulting in the
destruction of tumor cells.
Among these the cell mediated immune response
plays a major role.
Many tumors have been shown to induce tumor
specific CTLs that recognize tumor antigens
presented by class-I MHC on the tumor cells.
ROLE OF NK CELLS
The recognition of tumor cells is not MHC
restricted. Therefore, the activity of these cells does
not change by the expression of MHC molecules.
Fc receptor present on the NK cells binds to
antibody coated tumor cells leading to ADCC.
ROLE OF MACROPHAGES
Macrophages are observed to cluster around tumors
and their presence is often cause tumor regression.
They carry out the same function as NK cells with
the help of Fc receptor.
These cells carry out their antitumor activity by
secreting lytic enzymes, reactive N2 and O2
intermediates, cytokine called Tumor Necrosis
Factor(TNF-α) that have potent antitumor activity.
ELIMINATION OF TUMOR CELLS
Over the past decade there has been notable progress in the concept of cancer immunosurveillance and immunoediting based on
(i) Protection against development of spontaneous and chemically-induced tumors in animal systems.
(ii) Identification of targets for immune recognition of human cancer.
Cancer immunosurveillance:- It is an important host protection process that inhibits carcinogenesis and maintains regular cellular homeostasis.
Immunoediting:- It is a process by which a person is
protected from cancer growth and the development of
tumour immunogenicity by their immune system.
It has three main phases: elimination, equilibrium and
escape.
The elimination phase consists of the following four
phases:
Phase 1::The first phase of elimination involves the
initiation of antitumor immune response. During this
phase, the infiltrating lymphocytes such as the natural
killer cells and natural killer T cells are stimulated to
produce IFN-ϒ.
Phase 2:: Newly synthesised IFN-gamma inducestumor death (to a limited amount) as well as promotionof chemokines. These chemokines play an importantrole in promoting tumor death by blocking theformation of new blood vessels. Tumor cell debrisproduced as a result of tumor death is then ingested bydendritic cells, followed by the migration of thesedendritic cells to the draining lymph nodes.
The recruitment of more immune cells also occurs andis mediated by the chemokines produced during theinflammatory process.
Phase 3:: Natural killer cells and macrophagestransactivate one another via the reciprocal productionof IFN-gamma and IL-12.
In the draining lymph nodes, tumor-specific dendriticcells trigger the differentiation of Th1 cells which inturn facilitates the development of CD8+ T cells.
Phase 4:: tumor-specific CD4+ and CD8+ T cellshome to the tumor site and the cytotoxic Tlymphocytes then destroy the antigen-bearing tumorcells which remain at the site.
Equilibrium and Escape
Tumor cell variants which have survived theelimination phase enter the equilibrium phase. In thisphase, lymphocytes and IFN-gamma exert a selectionpressure on tumor cells which are genetically unstableand rapidly mutating.
Tumor cell variants which have acquired resistance
to equilibrium then enter the escape phase. In this
phase, tumor cells continue to grow and expand in
an uncontrolled manner and may eventually lead to
malignancies.
CANCER IMMUNOTHERAPY
Manipulation of Co-Stimulatory Signals Can EnhanceImmunity
Several research groups have demonstrated that tumorimmunity can be enhanced by providing the co-stimulatory signal necessary for activation of CTLprecursors (CTL-Ps).
As human melanoma antigens are shared by a numberof different human tumors, it might be possible togenerate a panel of B7-transfected melanoma cell linesthat are typed for tumor-antigen expression and forHLA expression. In this approach, the tumor antigen(s)expressed by a patient’s tumor would be determined,and then the patient would be vaccinated with anirradiated B7-transfected cell line that expresses similartumor antigen(s).
Enhancement of APC Activity Can Modulate TumorImmunity
One approach that has been tried is to transfect tumorcells with the gene encoding GM-CSF. Theseengineered tumor cells, when reinfused into the patient,will secrete GMCSF, enhancing the differentiation andactivation of host antigen-presenting cells, especiallydendritic cells.
Another way to expand the dendritic-cell population isto culture dendritic cells from peripheral-bloodprogenitor cells in the presence of GM-CSF, TNF-α,and IL-4. These three cytokines induce the generationof large numbers of dendritic cells.
A number of adjuvant, including the attenuatedstrains of Mycobacterium bovis called bacillusCalmette-Guerin (BCG) and Corynebacteriumparvuum, have been used to boost tumor immunity.
Cytokine Therapy Can Augment ImmuneResponses to Tumors
cytokines that have been evaluated in cancerimmunotherapy are IFN-α, β and ϒ; IL-1, IL-2, IL-4, IL-5, and IL-12; GM-CSF; and TNF. Althoughthese trials have produced occasional encouragingresults, many obstacles remain to the successful useof this type of cancer immunotherapy.
INTERFERONS
Large quantities of purified recombinant
preparations of the interferon, IFN-α, IFN-β, and
IFN-ϒ are now available, each of which has shown
some promise in the treatment of human cancer.
All three types of interferon have been shown to
increase class I MHC expression on tumor cells;
IFN-ϒ has also been shown to increase class II
MHC expression on macrophages.
TUMOR NECROSIS FACTORS
In some instances, the tumor necrosis factors TNF-α
and TNF-β have been shown to exhibit direct antitumor
activity, killing some tumor cells and reducing the rate
of proliferation of others while sparing normal cells.
In the presence of TNF-α or TNF-β, a tumor
undergoes visible hemorrhagic necrosis and regression.
TNF-α has also been shown to inhibit tumor-induced
vascularisation (angiogenesis) by damaging the
vascular endothelial cells in the vicinity of a tumor,
thereby decreasing the flow of blood and oxygen that is
necessary for progressive tumor growth.
REFERENCES
IMMUNOLOGY BY JANIS KUBY
ESSENTIAL IMMUNOLOGY BY IVAN ROITT
www.articles.cancer.images
THANK YOU!!!!!!!!!
