Bueter 17_8

Despite the radical surgical resection performed in patients with colorectal carcinoma, there is a high rate of tumor recurrence. Over an observation period of 3 years, 18% of the patients in our collective suffered a tumor relapse with local or distinct metastases after initial R0-resection. Some evidence suggests that this may be due to suppression of antitumor responses, a phenomenon that might be attributed to regulatory T cells. The aim of our study was to investigate the tumor-specific immune response depending on the UICC stage of patients with colorectal cancer. The cellular immune responses against defined antigens that are overexpressed in most of the patients with colorectal cancer were characterized. For this purpose, the tumor suppressor gene, p53, was chosen as the tumor-associated antigen that exhibits mutations and overexpression in up to 60% of colorectal carcinoma. We observed that p53 induced both IFN-Á and IL-10 secretion. The predominance of IL-10 production indicated that regulatory T cells directly participate in modulating the anti-tumor immune response. IL-10 levels in the blood as well as the expression of regulatory T-cell specific genes at the tumor site correlate with the UICC stage of the disease. These results may provide an explanation for the poor prognosis and increased recurrence rate in patients with advanced carcinoma. Introduction Mutations in the p53 gene are the most frequently reported somatic gene alterations in human malignancies. This results in an overexpression and cytosolic accumulation of the p53 protein, a phenomenon observed in more than half of all cancers. This ubiquitous expression of mutated p53 in tumors has prompted immunologists to use p53 as an antigen for the design of immunological therapies in cancer (1,2). The possibility of using wild-type (wt) p53 as an effective tool for immune intervention has been demonstrated in several mouse tumor models. Studies in rodents have demonstrated the immunogenicity of p53 during tumorigenesis and the induction of CD4+ and CD8+ T-cell responses directed to p53 determinants. While T-cell responses to p53 are consistently induced during cancer, they fail to eradicate tumors. It is noteworthy, however, that p53 immunization can lead to the differentiation of p53-specific CD4+ T helper and CD8+ cytotoxic T cells capable of rejecting tumors in mice (3,4). This supports the view that, in the absence of vaccination, anti-p53 T cells capable of rejecting tumors are either never activated or that they are suppressed by other T cells. In support of this view, our laboratory has previously reported that the vast majority of p53-specific CD4+ T cells expanding in mice with J774 sarcomas secrete type 2 cytokines (IL-4, IL-5, IL-10). This observation suggests that in tumor-bearing mice, while p53 is immunogenic it preferentially activates Th2/Treg (Tr1) cells, a response which does not lead to tumor rejection or even protects tumors from eradication by Th1 cells. It is still not clear whether polarization of anti-p53 response to Th2/Treg immunity during tumorigenesis represents a general phenomenon that is relevant to patients with different cancers. As we gain insights into these questions, we may design new methods of therapeutic intervention to manoeuvre the anti-p53 T-cell response towards effective tumor rejection. Mutations within the p53 gene have been demonstrated in a large proportion of colorectal cancer patients (5). Although MHC class II molecules are usually not expressed on the surface of solid tumors, which makes direct tumor eradication by CD4+ T helper cells impossible, there is cumulative evidence INTERNATIONAL JOURNAL OF ONCOLOGY 28: 431-438, 2006 431 T-cell response to p53 tumor-associated antigen in patients with colorectal carcinoma MARCO BUETER1, MARTIN GASSER1, NICOLAI SCHRAMM2, TATIANA LEBEDEVA3, GEORGES TOCCO4, CHRISTIANE GERSTLAUER2, MARTIN GRIMM2, EKATERINA NICHIPORUK2, ANDREAS THALHEIMER1, ARNULF THIEDE1, DETLEF MEYER1, GILLES BENICHOU4 and ANA MARIA WAAGA-GASSER2 Departments of 1Surgery I and 2Molecular Oncology and Immunology, University of Wuerzburg, D-97080 Wuerzburg, Germany; 3American Red Cross, New England Region, Dedham, MA 02026; 4CMI Laboratory, Massachusetts General Hospital, Department of Surgery, Transplantation Unit, Harvard Medical School, Boston, MA 02114, USA Received August 17, 2005; Accepted October 14, 2005 _________________________________________ Correspondence to: Professor Ana Maria Waaga-Gasser, Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Zentrum Operative Medizin (ZOM), Oberduerrbacher Str. 6, D-97080 Wuerzburg, Germany E-mail: [email protected] Abbreviations: TAA, tumor-associated antigen; MHC, major histocompatibility complex; DC, dendritic cell; CTL, cytotoxic T lymphocytes; PBLs, peripheral blood lymphocytes; UICC, International Union Against Cancer