So let’s turn now away from tumors of
the immune system itself, and ask the
question - does the immune system
naturally prevent or attack cancers?
Well the answer is yes, but
perhaps only for certain cancers.
So what is the evidence that the immune system
can actually recognize and attack cancers.
Well there’s an increased incidence of certain
cancers in patients with immunodeficiency,
including immunosuppressed transplant
patients as we’ve just mentioned.
The term immunosurveillance is used.
And this relates to the concept that cells
of the immune system patrol around the
body looking for cells that have become
abnormal because of malignant transformation.
Certainly the immune system can prevent
tumors that are linked to oncogenic pathogens.
And it’s now known that a number of organisms
can trigger the development of tumors.
So for example, the virus HTLV1 (Human T-cell Leukemia Virus-1)
as the name suggests, is responsible
for inducing T-cell leukemia.
Epstein-Barr virus can trigger a
number of tumors including Burkitt’s
lymphoma, nasopharyngeal carcinoma and post-transplant lymphoma.
The Human Papilloma viruses 16 and 18 are responsible
for triggering cervical cancer and penile cancer.
Hepatitis B virus and Hepatitis C virus are
linked to the development of liver cancer.
And the bacterium Helicobacter pylori can
trigger the development of stomach cancer.
So it’s quite clear in these kind of situations where
infectious agents are linked to the development of a tumor.
And after all the immune response has developed,
has evolved to fight infectious agents.
One can see a clear potential role for the
immune system in this kind of situation.
The term tumor antigen is used to describe
antigens that are associated with tumor cells.
Remember, tumors are
derived from normal cells.
Tumor-associated antigens are antigens that
are present either in or on normal cells.
And the immune system will normally be tolerant to
such antigens, because they’re normal self antigens.
In contrast, tumor-specific antigens
are restricted to tumor cells, and
the immune system may well not be
tolerant to such antigens; perhaps
arising by mutations in a gene that
then encodes a different form of a
protein to which the individual has not
been made immunologically tolerant.
There are a number of different
types of tumor antigen.
Some of the products have mutated
oncogenes or tumor suppressor genes.
Examples of ongogene products include RAS mutations
that are seen in around about 10% of human
carcinomas, the p210 product of the Bcr/Abl rearrangements
that can occur in chronic myeloid leukemia.
And mutations of tumor suppressor gene products, such a p53
mutations which are present in around about 50% of human tumors.
There are also tumor antigens that are unmutated
but overexpressed products of oncogenes.
The HER2/Neu antigen is a good example of this
that is seen in breast and other carcinomas.
Mutated forms of cellular genes that are not themselves
actually involved in tumorigenesis, can act as tumor antigens.
For example, various mutated proteins that are found in
melanomas that are recognized by cytotoxic T-lymphocytes.
And then we also have the products of genes
that are silent in most normal tissues.
For example, the cancer/testis antigens
expressed in melanomas and many carcinomas.
These antigens are normally expressed mainly in the
testis and placenta, but can get expressed in tumor cells.
Tumor antigens can also be normal non-oncogenic
proteins that are overexpressed in tumor cells.
For example, tyrosinase, gp100, and the MART antigens that are
found in melanomas and are normally expressed in melanocytes.
They can be the products
of oncogenic viruses.
For example, the papilloma virus E6 and E7 proteins
that are associated with cervical carcinomas.
EBNA-1 protein of Epstein-Barr virus, present in
EBV-associated lymphomas and in nasopharyngeal carcinoma.
Oncofetal antigens, such as the
carcinoembryonic antigen that’s present in
many tumors, and also expressed in liver
and other tissues during inflammation.
And another example of an oncofetal
antigen is alphafetoprotein.
Glycolipids and glycoproteins
can also act as tumor antigens.
For example, the GM2 and
GD2 antigens on melanomas.
And then finally, differentiation antigens that
are normally present in the tissue of origin.
For example, the prostate specific antigen
(PSA) present in prostate carcinomas.
And another example here would
be CD20 on B-cell lymphomas.
Anti-tumor immunity is essentially the same kinds
of responses that we see against infectious agents.
So antibody together with complement,
the antibody can bind to tumor
antigens present on the surface of
the tumor cell, activate complement.
And the membrane attack complex
can destroy the tumor cell.
Antibody dependant cellular cytotoxicity (ADCC),
again an antibody against a tumor antigen expressed
on the surface of the tumor cell can be recognized
by cells that are capable of mediating ADCC.
We call such cells, killer cells; really
they can be any cell in the immune
system that has an Fc receptor and
also is able to fuse toxic molecules.
And most cells in fact in the immune
system can carry out this function of ADCC.
There can be direct natural killer cell
cytotoxicity, where the killer activating receptors
on the surface of natural killer cells recognize
ligands on the surface of the tumor cell.
And finally there can be cytotoxic T-cells which recognize
tumor-derived peptides presented by MHC Class I molecules.
It’s very clear that immune system cells
are naturally present within tumors.
We can find T-cells, natural killer cells, macrophages, also
regulatory T-cells and myeloid derived
suppressor cells within tumors.
So T-cells, natural killer cells and macrophages
potentially could mediate a beneficial anti-tumor response.
One of the problems is that very often, these
other cell types, such as regulatory T-cells
and myeloid derived suppressor cells actually
dampen down the anti-tumor response.