Tumor Antigens

Author: Kornel Kusznieruk

Affiliation: University of Western Ontario
Date Published: Tuesday October 24th, 2006 @ 20:56:08 EST

Comments: No comments
From Category: Immunology


The rationale for immunotherapy, is dependent on the idea that
cancer must be recognised by the immune system. Cancer cells are derived from the
patient’s own tissue, therefore there has been some reluctance in believing that the
immune response can effectively control or even eradicate neoplasia. In the age of
molecular biology, great advances have occurred which demonstrated not only
immunological control of neoplasia, but also specific markers which are the target of
immune recognition. Such markers are useful not only for measuring the immune
response a patient may have against their tumor, but also for development of antitumor

The Mutator Phenotype

Cancer cells have a very high rate of mutation. This is partly accounted for by the fact
that many cancers have mutations in tumor suppressor genes such as p53. Cells with
mutated DNA are blocked from proliferating by p53, a protein that was also called
“guardian of the genome” because of its key function in maintaining genomic integrity
(1). If p53 it self is mutated or inactivated then the cell is able to acquire additional
mutations. Once this happens the cell is said to have a mutator phenotype (2). The
ability of cancer cells to mutate allows them to utilize any biological strategy they need in
order to survive and in most cases to kill the host.

Here is a sample of what mutations allow the cancer cells to do:

1. Resist normal antiproliferative signals such as TGF-β by mutating the receptor (3) or
transduction proteins linked to its signalling (4).

2. Evade apoptosis by mutating apoptosis-inducing receptors such as Fas (5).

3. Evade apoptosis by increasing activity of naturally occurring anti-apoptotic proteins
such as bcl-2 (6) or FLIP (7).

4. Proliferate in absence of external growth factor by a constitutively active:
a) Tyrosine kinases (8),
b) GTP protein (9),
c) Growth factor receptor (10,11).

5. Express the enzyme telomerase which allows cells to overcome the Hayflick limit and
continue dividing without the problem of telomere shortening (11a). The mutations of cancer cells allow them to be different than the noncancerous cells from which they originated. Targeting mutations that the cancer requires for proliferation and/or viability should be therapeutic since if the cancer cells mutate to evade the intervention, they will not be able to proliferate and/or remain viable. The flaw in this statement is that the cancer cells can try a new mutation. Or, cancer cells may mutate by altering the way in which they express the proteins on the cell surface, thus “hiding” them from our intervention. However, an immunotherapy that targets several mutations which
are needed for proliferation and/or viability will hopefully be efficacious, at least

Immune Recognition of Mutant Proteins

Although these molecular mutations exist, the question is whether immune response can
be induced against them. For the immune system to recognise mutant forms of protein,
these proteins must be expressed on the surface of the cancer cell. Classical immunology
teaches that intracellular proteins are digested into peptides and presented on MHC class
I to CD8 T cells. There have been some new papers describing the role of non-classical
MHC and molecules such as Rae-1 presenting tumor antigens to NK and gamma-delta T
cells (12-14). Regardless of the method of activation, immune response to tumor
antigens can be measured by T cell proliferation/cytokine production in response to in
vitro stimulation with the antigen, or by antibody responses.

Are there naturally occurring immune responses to oncogenically mutated proteins? Yes!

Immune Response to P53

Immune responses to wild-type p53 are not usually detectable, however antibody
response to mutant p53 was detected in patients with colorectal cancer (15), esophageal
cancer (16), breast cancer (17), ovarian cancer (18), and several other types (reviewed in

Interestingly, in some of these cases presence of antibody to mutated p53
corresponds with poor prognosis. An explanation for this may be that these antibodies
can not fix complement and therefore are unable to lyze the tumor. If this is the case,
than such antibodies may be deleterious to anticancer immune response by formation of
antigen-antibody complexes which have previously been demonstrate to stimulate the
cancer-promoting Th2 immune response (20, 21).

T cell responses have also been detected to both wild type and mutant p53 proteins. In
1995 Ropke et al used limiting dilution analysis to demonstrate the existence of MHC
class I restricted CD8 cells in the peripheral blood of healthy volunteers, which recognize
p53 peptides. These cells were found at a frequency of 1in 2 × 104 to 1.5 × 105 cells.
(22). In a more recent paper, p53-specific CD8 responses where seen only from
lymphocytes of patients bearing p53-overexpressing tumors (23). Why would healthy
individuals have T cells specific for a self peptide? A possible answer is that immune
response does not only recognize self vs non-self but also higher levels of self proteins.
In the case of p53, immunity can be increased by vaccination. DNA vaccines comprising
of the p53 gene under control of a strong promoter can elicit immunity to mutant p53
peptides in a murine model. The relevance of this experiment is seen by the observation
that immunized mice have protective antitumor immunity. Furthermore, immunogenicity
can be enhance by fusing a portion of the p53 gene with an endoplasmic reticulum
targeting sequence (24).

Immune Response to Telomerase

Telomerase is a ribonucleoprotein with enzymatic activity that is expressed in over 90%
of cancers and on very few non-cancerous cells. Targeting of telomerase has been
attempted by at the gene level by antisense oligonucleotides (25), as well as at the protein
level by pharmacological inhibitors (26). Unfortunately, both of these strategies are in
preclinical phases of development and potential problems of delivery and toxicity exist.
A more attractive idea would be to stimulate immune response against telomerase. The
first problem is that telomerase is expressed embryonically, and therefore a possibility
exists that it is hard, if not impossible to break tolerance against it. Fortunately, it is possible. By transfecting dendritic cells with mRNA encoding the polypeptide portion of
telomerase called TERT, and then immunizing mice with these dendritic cells,
investigators were able to induce CD8 cytotoxic T cells which recognized and lysed a
variety of different tumors. Human DC transfected with TERT were able to stimulate
human CD8 cells to lyse tumor cell lines in vitro (27). Vonderheide et al recently
demonstrated that it is equally feasible to raise TERT-specific CD8 cells from cancer
patients and healthy controls by ex vivo stimulation with TERT peptides. These cells are
able to lyse cell lines and primary tumor samples in an HLA-A2 restricted manner (28).

Mutant Ras

Ras is a molecular switch involved in proliferation and activation of a variety of cells.
Activated Ras signalling occurs when Ras is bound to GTP. GTPase activating proteins
(GAP) are responsible for changing Ras from its activated GTP bound form to its inactive
GDP bound form. Many types of cancers are associated with a mutant Ras that is
constitutively active. Several approaches have been used to target mutated Ras proteins
including antisense (29-31) and viruses which selectively kill cells expressing activated
Ras (32). Serum antibodies have been detected in women with precervical cancer lesions
but not in healthy women. Interestingly, the antibodies were directed against wild-type
Ras (33). A common activating Ras mutation in colon cancer is the substitution of
aspartic acid at amino acid position 12. Out of 160 patients with colon cancer 51
possessed antibodies to this form of Ras whereas only 1 out of 40 healthy controls had
this type of antibody. The isotype of the antibody was IgA which is a noncomplement
fixing type of antibody (34).

MHC class II restricted T cells have been found in peripheral blood of healthy individuals
which specifically recognize Ras with a substitution for aspartic acid on residue 12 (35).
These T cells are CD4 positive and do not possess cytotoxic activity. Therefore it would
be more desirable to determine whether CD8 cells can be raised to mutant Ras. By
immunizing patients with mutant Ras peptides followed by in vitro restimulation, it was
possible to raise both CD4 and CD8 cell lines which had specificity for mutant but not
wild-type Ras (36). In a feasibility study immunization with mutant Ras peptides
together with the dendritic cell stimulating cytokine GM-CSF, it was possible to induce
CD8 response to mutant Ras as demonstrated by positive skin reaction (37).

MAGE Antigens

Terry Boon and colleagues screened tumor cDNA libraries using T cell clones from
tumor patients. This lead to the identification of MAGE, a protein expressed in
melanoma cells and some other types of cancer but not expressed in normal tissue with
the exception of the testis and the placenta (38). Subsequently, other tumor specific
genes of the MAGE family (more recently called cancer-testis antigens) were identified
such as BAGE (39) and GAGE (40). About 50% of melanoma patients express one or
more of these genes. Expression of MAGE is suppressed by DNA methylation in adult
tissues. Treatment of noncancerous cells such as primary fibroblasts with the DNA
methylation inhibitor 5-aza-2’-deoxycytidine induces re-expression of MAGE (41).
MUC-1, an antigen associated with epithelial cancers is also re-expressed due to
hypomethylation of the gene only in the cancerous state (41a). While de-methylation is
used by cancer cells to turn on MAGE expression, cancer cells also specifically methylate
portions of the gene for MHC class I (42) in order to decrease immune recognition of
potentially immunogenic antigens. In a personal communication, although I forgot the
source, it was stated that the suppressed levels of TAP in cancer cell lines is due to DNA

Peptides derived from the MAGE protein have been demonstrated to induce specific
immune response in the clinical setting, occasionally with therapeutic benefit. Out of 25
HLA-A1 positive metastatic melanoma patients vaccinated with MAGE-3 peptides, 7 had
significant tumor regressions with two patients remaining free of disease for more than
three years (43,44). Partial regression of metastasis in melanoma was also achieved by
treatment of patients with dendritic cells pulsed with MAGE peptides (45,46). In vivo
expansion of MAGE-specific CTLs in response to vaccination has been demonstrated in
a clinical setting using tetramer technology (47). Antibody responses have been detected
to MAGE and other members of the cancer-testis antigen family in patients with
oesophageal, gastric and breast carcinomas (48).

Other Antigens

There are many, many other antigens that are found on tumors. The purpose of this book
is to throw ideas around, therefore I did not bother to go through all of the tumor specific
antigens. There are also antigens which are not tumor specific but tumor associated. One
example is tyrosinase, an enzyme which is involved in melanin production by normal
melanocytes. This enzyme is also expressed in melanoma cells and therefore contributes
to their immunogenicity (49). The fact that immune responses can be induced to
tyrosinase support the idea previously stated that the immune response may not only
discriminate between self and non-self but also between levels of self protein, or even
perhaps the context in which self protein is seen by the immune response. Other tumor
associated antigens include prostate specific antigen (PSA) and prostatic acid
phosphatase (PAP). Immune response to both of these proteins by vaccination has been
elicited, and in the case of PAP demonstrated some clinical efficacy (50-52).
Glycolipids on the surface of cancer cells such as the gangliosides GM2 and GD3 seem
to be specific to cancer cells. Complement-fixing antibodies to both of these gangliosides
have been elicited in human cancer patients although therapeutic effects are still
forthcoming (53,54).

Peptides from the protein product of the chronic myeloid leukaemia-specific oncogene,
bcr-abl, have been demonstrated immunogenic (55-58). In this type of leukaemia,
treatment of post-bone marrow transplant relapsed patients with donor-specific
leukocytes is effective in inducing long-term remission (59). The possibility of immune
response against bcr-abl derived peptides mediating these remissions should be
investigated. If it is possible to induce therapeutic immune response to bcr-abl derived
peptides, this would be an ideal target since leukemic cells in which expression of this
gene is blocked by antisense oligonucleotides undergo apoptosis (60). The key role of
bcr-abl in leukaemia is further demonstrated by observations that transfection of normal
human CD34 stem cells with this oncogene induces leukaemia-like properties in these
cells (61).


So what does this tell us?
First, there is such a thing as cancer-specific proteins. Sure, some may say that immune
response does not control cancer because if there indeed is recognition of all these
cancer-specific antigens, then why does cancer arise. To this I dare the detractor to ask a
transplant surgeon what the rate of tumors is in immune suppressed patients. The rate of
tumors in these patients are much higher compared to the normal population. And the
tumor types are diverse and not restricted only to hematological one.
Second, immune response to these proteins can be induced.
Third, in subsets of individuals immune response correlates with prognosis. In the case
of some patients with antibodies to p53, immune response can correlate with poor
prognosis, whereas in patients vaccinated with peptides of MAGE, immune response can
lead to regression. Several questions need to be answered:
1. Why is it that immune response allows for cancers to begin in the first place?
2. What are the mechanisms by which tumor cells evade immune responses?
3. Are there better methods of immunization for increased clinical efficacy?
4. Is the systemic immune response of the cancer patient too weak to destroy the
offending antigen, even if recognition occurs?
5. What combinations of treatments can be used for maximal therapeutic gain?
Actually, there are probably a lot more questions, but throughout this book I hope to
answer some of them.


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