Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

24 2 Serological Determinants On Tumor Cells
2.7
Functional Significance of SEREX Antigens
Antigens with a known function identified by SEREX include HOM-RCC-3.1.3 [7],
which was shown to be a novel member of the CA family, designated as CA XII.
Overexpression of this transcript was observed in 10% of renal cell cancers (RCC),
suggesting a potential significance in this tumor type. In fact, the same transcript
was cloned shortly thereafter by another group based on its downregulation by the
wild-type von-Hippel-Lindau tumor suppressor gene, the loss of function of which is
known to be associated with an increased incidence of RCC [25]. Since the invasiveness
of RCC cell lines expressing CA XII has been shown to be inhibited by acetazolamide
[26], CA XII might be exploited therapeutically. Bax inhibitor protein 1, which
was found to be overexpressed in gliomas, is an anti-apoptotic molecule [21].
The first cancer testis antigen to which a physiological function could be ascribed is
HOM-TES-14, which is encoded by the SCP-1 gene [10]. SCP-1 is known to be selectively
expressed during the meiotic prophase of spermatocytes and is involved in the
pairing of homologous chromosomes, an essential step for the generation of haploid
cells in meiosis I. Transfection of diploid cell lines with SCP-1 induces polyploidy,
suggesting that the aberrant expression of this meiosis-specific gene product in the
somatic cells of human tumors is involved in the induction of chromosomal instabilities
in cancer cells (unpublished data).
2.8
Reverse T Cell Immunology
SEREX may also be useful for the analysis of the CD4 + and CD8 + T cell repertoire
against tumor antigens, in a strategy which is also known as ªreverse T cell immunologyº.
Serologically defined antigens are valuable tools for the identification and
determination of peptide epitopes reacting in the context of MHC molecules with
the antigen-specific receptor of T cells, since the isotope switching and the development
of high-titered IgG in vivo requires cognate CD4 + T cell help. Several CD4 +
binding epitopes of the NY-ESO-1 antigen have been identified [27]. With regard to
CD8 + T-lymphocytes that recognize SEREX antigens, CTL responses have been demonstrated
for NY-ESO-1 and HOM-MEL-40 [27, 28].
2.9
Towards a Definition of the Human Cancer Immunome
SEREX allows for the identification of an entire profile of antigens using the antibody
repertoire of a single cancer patient. The analysis of a variety of neoplasms demonstrated
that all hitherto investigated neoplasms are immunogenic in the tumorbearing
host and that immunogenicity is conferred by multiple antigens. For the systematic
documentation and archivation of sequence data and immunological charac-