Immunology of

Cancer

Why Immunology?

The immune system’s influence on the

development of cancer can be seen in

immunocompromised patients.

a.

5% persons with congenital immunodeficiencies develop
cancer

(200 x rate)

b.

immunosuppresed transplant patients (rate 80 x)

c.

AIDS
lymphomas (activated B cells)
XLP + EBV - chronic infectious mononucleosis

or

- malignant lymphomas

So basically in healthy

individuals the immune

system recognizes tumor

cells as foreign and

destroy them before they

have a chance to multiply.

How does the immune

system recognize tumor

cells?

The immune system can distinguish
between normal and transformed
cells by:

• Tumor specific antigens (TSA)-present on

tumor cells, and not on normal cells.

• Tumor associated antigens (TAA)-present on

tumor cells and some normal cells.

•

40% melanomas

•

20% breast ca express

MAGE-1

•

30% lung small cell ca

Examples of tumor
antigens

Renal cell carcinoma 70% express
GP250

The membrane of the normal cells & cancer
cells

How the immune system “kill” the
cancer cell.

Cellular Effectors that Mediate Immunity

1.Cytotoxic T lymphocytes-protective role against

virus-associated neoplasms (EBV, HPV)

2.Natural killer cells (NK)-lymphocytes capable of

destroying tumor cells w/o prior sensitization - first
line of defense against tumors. After activation
with IL-2, NK lyse a variety of tumors (even if they
appear to be non-immunogenic to T cells.
T cells

complementary anti-tumor mechanisms

NK cells

Cellular Effectors that Mediate Immunity

3. Macrophages-activated exhibit selective

cytotoxicity against tumor cells.
T cells
NK cells

collaborate in anti-tumor reactivity

Macrophages
(e.g. INF- secreted by T and NK cells, activator of

macrophages). Kill by production of reactive
oxygen , or secretion of TNF-

4. Humoral mechanisms

activation of

complement

induction of

ADCC

(antibody-

dependent cell cytotoxicity):

by NK

cells

Antibody-dependent cellular
cytotoxicity (ADCC)

Tumor
cell

Granzymes pass through the pores and activate the
enzymes that lead to apoptosis of the infected cell by
means of destruction of its structural cytoskeleton
proteins and by chromosomal degradation. As a result,
the cell breaks into fragments that are subsequently
removed by phagocytes. Perforins can also sometimes
result in cell lysis.

The Fab portion of the
antibody binds to
epitopes on the
"foreign" cell. The NK
cell then binds to the
Fc portion of the
antibody. The NK cell is
then able to contact
the cell and release
pore-forming proteins
called perforins,
proteolytic enzymes
called granzymes, and
chemokines.

As a result, the cell breaks into fragments that are
subsequently removed by phagocytes. Perforins can also
sometimes result in cell lysis.

The NK cell releases
pore-forming proteins
called perforins,
proteolytic enzymes
called granzymes, and
chemokines.
Granzymes pass
through the pores and
activate the enzymes
that lead to apoptosis
of the infected cell by
means of destruction
of its structural
cytoskeleton proteins
and by chromosomal
degradation.

Possible Effector Mechanisms in Tumor

Immunity

Humoral

Opsonization and

phagocytosis

Complement-mediated lysis
Loss of cell adhesion

(antibody dependent)

Cell-Mediated

Cytotoxicity

T Cell
Antibody-dependent

cytotoxicity

NK
LAK (lymphokine-activated

killer) cells

Macrophages (macrophages

can be activated by
lymphokines)

The antitumoral T-lymphocyte bind with the

tumoral cell

The search of tumor cells with a

help of the antitumoral T-

lumphocytes

The destruction of tumor

cells by T-lymphocyte

HOW THE T CELL DESTROYS CANCER

If our immune system

can destroy tumor cells

then why do we have

cancer?

There is a selection for tumor cells that among other
things:
1. Avoid the immune response by being non-
immunogenic, selective outgrowth of antigen
negative variants.
2. Loss or reduced expression of HLA antigens.
2. Immunosupression, producing anti-inflamatory
cytokine such as TGF-1.
3. Induce apoptosis of immune cells (NK cells,
Cytotoxic T lymphocytes, Helper T lymphocytes)
4. No costimulation, no sensitization

Escape Mechanisms from Immuno

Surveillance

Tumor Evasion of Cytotoxic T lymphocytes (CTL) eg.

Tumor Evasion of Cytotoxic T lymphocytes (CTL) eg.

The Tumor cell can also induce apoptosis
(programmed cell death) of T lymphocytes.

5 min after
contact

45 min
after
contact

T cell

tumor

Apoptoti
c T cell

tumor

Tumor cells
can destroy T
cells by the
Fas/FasL (Fas
ligand)
pathway or
with the use
of
gangliosides.

So the Tumor cell can

avoid the immune system’s

response by “hiding”,

“pretending to be normal”,

or “killing” the immune

cells.

OK, so what now?

How do we make the

immune system recognize

and destroy the tumor

cells?

The Challenges of The immune

system

1. How to identify and specifically

respond to millions of different antigens

2. How to distinguish between foreign

(tumor) and self antigens

3. How to optimally and appropriately

respond to tumors

The players, or the cells of the

immune system

• Lymphocytes (B and T cells): Determining

the specificity of the immune response

• Monocytes/Macrophages and Dendritic

cells (Antigen presenting cells - APC):
presentation of antigen on the major
histocompatability complex (MHC).

• Natural Killers

• Mast cells and Basophils

• CD4

+

T cells- T helper cells

CD4 interacts with MHC II that process
Ag from the environment

• CD8

+

T cells- cytotoxic cells

CD8 interacts with MHC I that presents

intracellular antigens.

The immune response takes

place in specific tissues

• The cells of the immune system are

found in peripheral organized tissues:

• Recirculating in the blood and lymph
• Lymph nodes
• Spleens

It is within these tissues that the immune

response occur

The immune response

1. Humoral: B-cells/Th2

Production of Antibodies that

specifically bind antigens. Initiates the

clearance of the antigen by phagocytes

and the complement system.

2. Cellular response: T-cells/Th1

Specialized cells that respond

specifically to antigen on cell surface,

resulting in killing those cells and

activating other cells that clear the

antigen.

In cancer treatment, often

surgery, chemotherapy,

and radiotherapy does not

work eg. in malignant

melanoma.

Thus a new type of therapy

is thought. One of this is

IMMUNOTHERPY.

Cancer Immunotherapy

Aim:

To activate the patient’s

immune system to specifically

recognize and destroy human

tumor cells

Since the first use of smallpox vaccine in the late
1700s, therapies have been used to activate the
immune system to combat various infectious
diseases. Growing understanding of how cancer
cells challenge the immune system has given
hope for therapeutic vaccines that maybe able to
overcome the limitations of current cancer
therapies.

Therapeutic approaches for cancer
immunotherapy generally fall in to three
categories:

I.

Passive Immuntherapy

II.

Non-specific Immunotherapy

III.

Active Specifuc Immunotherpy

Passive Immunotherpy

Uses monoclonal antibodies to selectively
interfere with tumor cell functioning. What is
needed is

1. A monoclonal antibody specific for the cancer
cell attached to

2. A cytotoxic drug, toxin or radioactive atoms that
kills the cell once it gets inside.

Non-specific Immunotherapy

Uses compounds including cytokines such as
interferon, interleukin and BCG, that upregulates
the general immune system response to cancer.
However, cytokine therapy suffers the same
limitations as chemotherapy in that cytokines lack
selectivity and are associated with significant
toxicity. Eg. Interferon and IL-2 used in the
treatment of melanoma have significant side
effects in most patients.

Active Specific Immunotherapy

Purified antigens, peptides, gene-based systems, or
antigens contained in whole cells or cell lysates are
used in active specific immunotherapy for cancer.
They are also called therapeutic cancer vaccines.

Unlike chemotherapy, active specific
immunotherapy does not directly kill cancer cells,
but generate a specific and targeted humoral
and/or cellular immune response against the
cancer and stimulate an increase in the number
and type of immune cells and antibodies capable of
responding to cancer. Also therapeutic cancer
vaccines may activate the immune system to
overcome the immunosuppression caused by tumor
growth and development.

Cytokines that have been shown to

inhibit tumor establishment

• IL-2 - Activates T cell, NK cells and

marophages

• IL-4 - Activates T and B cells
• IL-6 - Augments B cell growth and Ab

production

• IL-12 - Stimulate T and NK cells to produce IFN-



• IL-15 – Activates T cell, NK cells, LAK, and TIL
• GM-CSF - Accelerates hematopoietic recovery

after

chemotherapy

• TNF- - Stimulates target cells, induces MHC
• IFN- - Induce cytotoxicity

Immunotherapy is still in its
infancy but holds great
potential.

Well anyway, Good luck on
your USMLE and the Match!