Tumour-inhibitory and antimetastatic effects of IL-2 in mice carrying MHC class I- tumours of HPV16 origin.
ABSTRACT Oncogenic, moderately immunogenic, MHC class I- and class II-, B7-, MK16/1/III ABC (MK16) cells were previously established by co-transfection of HPV16 E6/E7 and activated H-ras oncogene DNA into C57BL/6 kidney cells. Subcutaneous transplantation of these cells produced progressively growing local neoplasms which metastasized spontaneously to lungs and lymph nodes. The MK16 cells were implanted into syngeneic mice and used to examine whether the tumour lacking the signal molecules required for the induction of and sensitivity to T cell immunity is susceptible to local IL-2 treatment and IL-2 gene therapy. Peritumoural administration of human rIL-2 or murine IL-2 gene-modified MK16 tumour vaccine inhibited growth of subcutaneous MK16 tumour transplants and reduced the number of their lung metastases. Spleen cells from MK16 tumour-immunized mice were not cytolytic when allowed to react with the MK16 target cells, although they efficiently lysed the MHC class I+ malignant TC1 cells, obtained from C57BL/6 lung cell cultures after transfection with the same plasmids as those used for the derivation of the MK16 cells. However, when the MK16 cells were cultivated in vitro in the presence of IFNgamma, they acquired, together with the expression of MHC class I molecules, the sensitivity to the cytolytic effect of spleen cells from the MK16 tumour-immunized mice. These results indicate that experimental tumours which are MHC class I- and mimick in this respect a high proportion of human HPV16-associated carcinomas are suitable for IL-2 treatment.
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ABSTRACT: The adaptive immune system seems to play an essential role in the natural course of ovarian cancer. Aim of this study was to establish whether disease-specific survival for patients expressing the tumour antigen p53 is influenced by MHC class I expression or the presence of p53 autoantibodies (p53-Aab). P53 and MHC class I expression were analysed in ovarian cancer tissue of 329 patients by immunohistochemistry using tissue microarrays. For 233 patients, pre-treatment serum samples were available to study the presence of p53 autoantibodies by ELISA. Data were linked to clinicopathological parameters and disease-specific survival. P53 overexpression, MHC class I down-regulation in neoplastic cells and serum p53 autoantibodies were observed in 49.4, 38.9 and 15.9% of patients, respectively. MHC class I down-regulation in p53-overexpressing tumours correlated with a 10-month reduced disease-specific survival in univariate analysis (log-rank 4.10; p=0.043). p53-Aab were strongly correlated with p53 overexpression (p<0.001), but did not influence disease-specific survival. As the prognosis of patients with p53-overexpressing ovarian cancer is affected by the MHC class I status of tumour cells and ovarian cancer patients can generate immune responses to the p53 tumour antigen, the further development of immunotherapy should evaluate strategies to improve MHC class I expression by tumour cells to facilitate antigen presentation in an attempt to increase clinical responses.Gynecologic Oncology 07/2008; 110(3):365-73. · 3.93 Impact Factor
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ABSTRACT: Cells of transplantable MC38 colon carcinoma of C57BL/6 mice were adapted to growth in vitro as the MC38/0 cell line. Along the establishing process, MC38/0 cells preserved their tumorigenicity. After transduction with a retroviral vector carrying murine interleukin 12 (mIL-12) genes and further selection, stable MC38/IL-12 transductant cells were obtained. These cells produced IL-12 (approx. 2500 ng/ml/5x10(5) cells/48 h) as evaluated in the optimized bioassay. After subcutaneous inoculation into syngeneic mice, the IL-12-modified cells demonstrated reduced tumorigenicity as compared to parental MC38/0 cells. Mice that rejected the MC38/IL-12 tumour became protected against subsequent challenge with MC38/0 cells. The obtained data indicate that the IL-12-transduced murine colon carcinoma cells could be used both as a model tumour for the study of mechanisms of anticancer immunity and/or as an adjuvant to cancer vaccines.Folia biologica 02/2004; 50(1):7-14. · 1.22 Impact Factor
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ABSTRACT: MHC class I downregulation is a general mechanism by which tumor cells can escape from T-cell-mediated immunity. This downregulation also represents a serious obstacle to the development of effective antitumor immunotherapy or vaccination. Therefore, successful immunotherapeutic and vaccination protocols should be optimized against tumors with distinct cell surface expression of the MHC class I molecules. Mechanisms leading to protective immunity may vary in different models with respect to the particular tumors (e.g., in their levels of residual expression of the MHC class I molecules on tumor cells or inducibility of MHC class I expression). Notably, both CD8(+) cell-mediated immunity and MHC class I-unrestricted mechanisms can take place against MHC class I-deficient tumors. Since MHC class I downregulation is frequently reversible by cytokines and also by the activation of epigenetically silenced genes, an attractive strategy is to elicit specific cell-mediated immunity combined with restoration of MHC class I expression on tumor cells.Future Oncology 10/2010; 6(10):1577-89. · 3.20 Impact Factor