Pierre
van der Bruggen, Vincent Stroobant, Aline Van Pel, and Benoît
Van den Eynde
Human
tumor antigens recognized by CD4+ or CD8+ T cells are being defined
at a regular pace. We have tried to classify them into four major
groups on the basis of their expression pattern. This classification
may appear arbitrary and indeed reflects the biases derived from
our own studies, which have mostly dealt with melanoma. The interest
of such a classification is practical, as the expression pattern
of the antigens is the critical factor determining their potential
usefulness for cancer immunotherapy. Although we have tried to
incorporate most tumor antigens identified so far, we have certainly
missed some. We will try to update the data regularly and we encourage
investigators to submit additional information to be included
in the database.
A first distinction can be made between unique antigens (Table
1) and shared antigens. The shared antigens can be further divided
into tumor-specific antigens (Table 2), differentiation antigens
(Table 3) and overexpressed antigens (Table 4). The tables provide
the following information for each antigen:
(a) a GeneCard link for the encoding gene and/or the parent
protein,
(b) the HLA presenting molecule and its frequency in Caucasians,
(c) the peptide sequence and its position in the protein sequence,
(d) the method used to isolate the CTL recognizing the antigen,
(e) a PubMed link to the relevant reference.
Each line corresponds to a peptide, considered to be a tumor antigen
based on its recognition by T lymphocytes that also recognize
tumor cells expressing the parent protein. As indicated in the
penultimate column, such T lymphocytes have been derived in
vitro by stimulating lymphocytes either with autologous tumor
cells or with antigen-presenting cells pulsed with peptide or
engineered to express the relevant gene. The peptide indicated
is usually the shortest synthetic peptide recognized by the T
cells.
We
have included in the database only the antigenic peptides that
fulfill the following requirements:
(a) isolation of stable human T lymphocyte clones or lines recognizing
the peptide,
(b) identification of the peptide recognized by the T cells,
(c) identification of the HLA presenting molecule,
(d) evidence that the peptide is processed and presented by
tumor cells. This implies showing recognition of tumor cells
expressing the relevant gene and HLA molecule by the T cells.
When a polyclonal T cell line is used rather than a clone, it
is essential to demonstrate that the CTLs that lyse the tumor
cells are the same as those that recognize the peptide. This
can be done by "cold target inhibition" experiments using peptide-pulsed
cold targets. Other means of proof are also possible, such as
the testing of stable transfectants of tumor cells with the
sequence encoding the parental protein. In the case of CD4 T
lymphocytes that do not recognize tumor cells directly, the
fact that the peptide is processed can be shown by testing antigen-presenting
cells loaded with the recombinant protein or a control protein
produced in the same organism, or loaded with lysates of cells
transfected or not with the relevant coding sequence.
(e) the characterization of peptides recognized by CD8 T cells
should include the identification of the shortest peptide recognized
and a titration showing a clear recognition of this peptide
at doses below 1 µM. When this is not the case, the actual
peptide recognized by the CTLs on the tumor cells may be different
due, for example, to a post-translational modification or a
cross reaction of the CTLs with an irrelevant peptide.
(f) a certain level of tumor- or tissue-specificity should be
documented, as ubiquitous antigens do not qualify as tumor antigens.
This can be done with gene expression, protein expression or
lymphocyte recognition data, which should ideally be corroborative.
Unique antigens result from point mutations in genes that are
expressed ubiquitously (Mutation).
The mutation usually affects the coding region of the gene and
is unique to the tumor of an individual patient or restricted
to very few patients. Some of these mutations may be implicated
in tumoral transformation. Such antigens, which are strictly tumor-specific,
may play an important role in the natural anti-tumor immune response
of individual patients, but most of them cannot be easily used
as immunotherapeutic targets because they are not shared by tumors
from different patients.
On the other hand, shared antigens are present on many independent
tumors. They can be further divided into three groups. One group
corresponds to peptides encoded by "cancer-germline"
genes, such as MAGE, which are expressed in many tumors
but not in normal tissues (Shared Tumor-specific).
The only normal cells in which significant expression of such
genes has been detected are placental trophoblasts and testicular
germ cells. Because these cells do not express MHC class I molecules,
gene expression should not result in expression of the antigenic
peptides and such antigens can therefore be considered as strictly
tumor-specific. The genes encoding such antigens have also been
referred to as "cancer-testis" (CT) genes.
A second group of shared tumor antigens, named differentiation
antigens, are also expressed in the normal tissue of origin of
the malignancy (Differentiation).
The paradigm is tyrosinase, which is expressed in normal melanocytes
and in most melanomas. Antigens of this group are not tumor-specific,
and their use as targets for cancer immunotherapy may result in
autoimmunity towards the corresponding normal tissue. In the case
of melanocytes, the risk of inducing severe side effects appears
minimal, and could be limited to the appearance of vitiligo. More
serious concerns about autoimmune side effects apply to carcinoembryonic
antigen (CEA), an oncofetal protein expressed in normal colon
epithelium and in most gut carcinomas. Autoimmune toxicity should
not be an issue, however, in situations where the tissue expressing
the antigen is dispensable or even resected by the surgeon in
the course of cancer therapy, as would be the case for prostate
specific antigen (PSA).
It is much more difficult to make predictions regarding the safety
of targeting shared antigens of the third group, which are expressed
in a wide variety of normal tissues and overexpressed in tumors
(Overexpressed). Because a minimal
amount of peptide is required for CTL recognition, a low level
of expression in normal tissues may mean that autoimmune damage
is not incurred. However, this threshold is difficult to define,
as is the normal level of expression of those genes for each cell
type.
A
large series of additional peptides have been described which
have not (yet) been included in the tables because formal evidence
to fulfill one or several of the aforementioned criteria has not
been provided. The relevant references are listed (Potential).
A number of viruses, such as the Epstein-Barr virus (EBV) and
human papilloma virus (HPV), are associated with human malignancies.
The antigenic peptides encoded by viral genes have not been included
in the database, despite their high potential as targets for immunotherapy.
References
1. Van den Eynde BJ, van der Bruggen P. T cell-defined tumor antigens.
Curr Opin Immunol 1997; 9: 684-93. (PMID: 9368778)
[PubMed]
2. Houghton AN, Gold JS, Blachere NE. Immunity against cancer:
lessons learned from melanoma. Curr Opin Immunol 2001;
13: 134-40. (PMID: 11228404) [PubMed]
3. van der Bruggen P, Zhang Y, Chaux P, Stroobant V, Panichelli
C, Schultz ES, Chapiro J, Van den Eynde BJ, Brasseur F, Boon T.
Tumor-specific shared antigenic peptides recognized by human T
cells. Immunol Rev 2002; 188: 51-64. (PMID: 12445281)
[PubMed]
4. Parmiani G, De Filippo A, Novellino L, Castelli C. Unique human
tumor antigens: immunobiology and use in clinical trials. J
Immunol 2007; 178: 1975-9. (PMID: 17277099) [PubMed]
Contact
Address
correspondence to:
Ludwig Institute for Cancer Research
74 avenue Hippocrate, UCL 74.59
B-1200 Brussels
Belgium
