Bueter M, Gasser M, Meyer D, Gassel AM1, Thiede
A, Waaga-Gasser AM
Dept.
of Surgery, Molecular Oncoimmunology; 1Dept. of Pathology, Univ.
of Wuerzburg, Germany
waaga-gasser@chirurgie.uni-wuerzburg.de
Anti-tumor
specific immune responses are modulated via different escape mechanisms abrogating
tumor destruction. We analyzed p53 specific immune responses in colorectal
cancer patients (n=24) depending on UICC stage and characterized their regulatory
T cell functions independent of the p53 mutational status. Peripheral blood
lymphocytes (PBMCs) were stimulated with 10 pools of synthetic overlapping
peptides of the wild-type (wt) p53 sequence and Il-10/IFN-γ expression was
assessed (ELISA, ELISPOT). PBMCs, tumor specific cells, and tumor specimens
were further characterized (cytospins, FACS, immunohistology). Lymphocyte stimulation with the peptides resulted in distinct
residues inducing a Th2 (IL-10, n=24) or Th1 (IFN-γ, n=10)
response. T cells from UICC III/IV patients expressed more IL-10 in response
to p53 peptide (residues 291-330) than those in UICC I/II (26 and 62 vs 14
spots/105 cells, n=7, respectively). In contrast, residues 331-370
led to IFN-γ production (no correlation between UICC and Th1 response). Increased
CD4+, CD25+, and CD56+ cells in the PBMCs, as well as intensified staining
for p53 (clone DO-7) were observed in patients expressing higher levels of
IL-10. Within the p53 protein sequence comparably more determinants
inducing a Th2 response were detected suggesting that the tumor specific response
to p53 depends on presentation/recognition of specific wt p53 residues. IL-10
production seems to overweigh IFN-γ indicating that specific p53 epitopes
may directly influence the outcome of immunological surveillance. This study
offers new insights in a possible mechanism facilitating the tumor to escape
immune surveillance by inducing rather a Th2 (tolerance) than Th1 type response
(destruction) through p53 overexpression.