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Cancer and the Immune System
Immunology
Cancer is altered self cells that have escaped normal
growth regulating mechanisms.
These cells give rise to clones of cells that can expand to a
considerable size, producing a tumor, or neoplasm.
• If it does not invade the healthy surrounding tissue it is
called benign.
• A tumor that continues to grow and becomes
progressively invasive is malignant
Malignant transformation of cells:
Transformation: is alteration of cell morphology & growth properties.
The changes in properties are:1. ↓ requirement for growth factor.
2. No longer anchorage-dependent.
3. They grow in a density-independent fashion.
4. They can subculture indefinitely (immortal).
Mutation of cells caused by various physical agents
(UV light & ionizing irradiation). Chemical agents (
alkylating agents). These will induce transformation
with 2 phases, which are:
A. Initiation, which involve change in the genome
but, does not in itself lead to malignant
transformation.
B. Promotion by promoters that stimulate cell
division & lead to malignant transformation.
These chemical & physical Ag that induce tu are called
carcinogen, of which, if it induces 2 separate tu at
different sites in the same patient → the tu Ag are
distinct, so, the immune response to one tu does not
protect against other tu. I.e. they were highly specific.
In contrast, in virally induced tu , the tu express tu Ag
that, were shared by all tu induced by the same virus,
even if in different site, i.e. there is cross-reaction,
while, tu cell induced by different viruses do not crossreact.
Tumor of immune system:
Classified into: 1. Lymphoma which, tend to proliferate as
solid tu.
2. Leukemia which, tend to proliferate as
single cell.
Oncogenes and Cancer Induction
Most, if not all, oncogenes (both viral and cellular) are
derived from cellular genes that encode various
growth-controlling proteins. Oncogenes and tumor
suppressor genes have been shown to play an
important role in cancerous process, by regulating
either cellular proliferation or cell death.
Cancer-associated genes can be divided into three
categories that reflect these different activities.
1. Induction of cellular proliferation. By proteins that,
function as growth factors or growth factor receptors.
Also proteins that function in signal-transduction
pathways or as transcription factors.
2. Inhibition of cell proliferation by proteins called tumor
suppressor genes, or anti- oncogenes. Inactivation of
these results in unregulated proliferation. For e.g. p53
which is nuclear phosphoprotein that inhibits formation
of small-cell lung cancer and colon cancers.
3. Regulation of programmed cell death as bcl-2 which is
suppressor of apoptosis.
Tu associated Ag: 2 types were detected which are:
• Tu specific transformation Ag (TSTA), which, is
unique to tu cell & not found in normal cell.
• Tu associated transplantation Ag (TATA), which is
not unique to tu but, may be protein that expressed
on normal cell also, which are:
1. Oncofetal Ag as, * Alpha-fetoprotein (AFP), that is
normally present only during fetal life so, if it ↑ in
adult life, it indicate liver cancer.
* Carcinoembryonic Ag (CEA)
which, if ↑ in adult so, indicate colorectal
carcinoma.
2. Over expression of normal Ag, as growth factor &
growth factor receptor.
The tumor Ag recognized by human T cells fall into
one of four major categories:
■ Ag encoded by genes exclusively expressed by
tumors.
■ Ag encoded by variant forms of normal genes that
have been altered by mutation.
■ Ag normally expressed only at certain stages.
■ Ag that are over expressed in particular tumors.
Mechanisms of tu immunity:
Tu can induce potent immune responses as:
1. It induce both humoral & CMI with, CMI plays a major role of
which; it will attack Tu cells & limit their proliferation. Some tu cell
can escape from immune response by modulation.
Tu Ag induce tu specific CTLs that, recognize tu Ag presented by class
I MHC on tu cell (but, there is ↓ in expression of class I MHC in a
number of tu so, it will limit the role of CTL in their destruction).
2.
Killer cell & macrophage are important in tu recognition, in
which, both recognize tu with MHC independence. So it recognize
tu even if, ↓ in MHC is present. As well, both cells have FC
receptor that can bind to Ab coated tu cell leading to ADCC.
3.
4.
NK cells, which act without Ab.
Tu Ag can stimulate the development of specific Ab, of which
some of them are cytotoxic, but others, called blocking Ab,
enhance tu growth by blocking recognition of tu Ag by the host.
5. The Role of Cytokines
– IFN-γ. This cytokine can exert direct anti-tumor effects
on transformed cells
enhanced class I MHC
expression
targets for CD8+ T cell recognition
and destruction
– IL-12 driving the development to T-cell pathways: this
cytokine encourages DCs to activate strong TH1 and CTL
responses (enhance anti-tumor immunity)
– TNF-α was named for its anticancer activity. When it was
injected into tumor-bearing animals, it induced
hemorrhage and necrosis of the tumor.
Tu evasion of the immune system:
1.
Anti-tu Ab can enhance tu growth because it act as blocking
factor.
2. Ab can modulate tu Ag. This is called Agic modulation.
3. Tu cell frequently express low level or even complete loss of
class I MHC & that will accompany progressive tu growth. So
absence of class I MHC in tu cell indicate poor prognosis.
4.
Tu cell may provide poor co-stimulatory signals, so poor
immunogenicity of tu.
5. Tu cell that decreased expression of ligands that bind
activating receptors on NK cells allows these cells to avoid NK
cell-mediated killing.
6. The up-regulation of anti-apoptotic mediators and the
expression of mutated or absent death receptors can lead to
tumors that are resistant to programmed cell death signals.
Cancer
immunotherapy:
Approach of treatment is
to augment natural
defense mechanisms
by:
• Manipulation of costimulatory signal
through providing
signal necessary for
activation of CTL
precursor.
• Enhancement of APC activity as for e.g. culture of dendritic
cell (from peripheral blood ) in the presence of GM-CSF, TNFα & IL-4. All these 3 cytokines induce the generation of large
number of dendritic cell.
• Cytokines therapy as,
A. IFN will ↑ class I MHC.
B. TNF- α & β which, have direct anti tu activity
C. IL-2: (in high concentration) will activate one type
of NK cell called LAK cell( lymphocyte activated
killer cell), which are activated NK cell with
TCR that kill tu cell & not normal cell.
So, Lymphocyte + IL-2 → LAK → tu cell destruction.
Also the tu contain specific lymphocyte that have
been infiltrated the tu & have antitu response.
These are called TILs (tu-infiltrating lymphocyte).
As well, IL-1, 2, 4, 5, 12. GM-CSF. All augment immune
response against tu. But the difficulty is that all
have S.E
•
1.
Monoclonal Ab as:
Anti growth factor receptor e.g, anti HER-2 for
breast cancer.
2. Anti to tu specific Ag, that is coupled with radioisotopes, which is called guided missile therapy.
3. Also the use of what is called immunotoxin
(diphtheria toxin ).
4. BCG vaccine used to boost tu immunity by
activating macrophage & ↑ the expression of
various cytokine.
Tu vaccine:
aim is to focus the cellular arm of immune system
against the tu – associated Ag that, exist in the
body. So if immune system recognizes this Ag, it will
act against it.
• So tu Ag + cell contain MHC I (dendritic cell) →
Hybrid → immunogen.
The advantage of this is that, the hybrid cell has the
Ag presenting capability of a dendritic cell but, also
contains the Ag from the patient’s tu cell, then
dendritic cell process tu Ag & present it to immune
system of the patient.