Gene Transfer of the Co‐Stimulatory Molecules B7‐1 and B7‐2 Enhances the Immunogenicity of Human Renal Cell Carcinoma to a Different Extent

Abstract

Stimulation of a specific antitumour immune response with recruitment and induction of T-cell effector functions represents an attractive concept in human cancer therapy. Different cytokines and the B7 costimulatory molecules are both able to provide proliferation and activation signals for T cells. In the present study, we first demonstrated the absence of both B7-1 and B7-2 expression in human renal cell carcinoma (RCC) cell lines. The lack of B7 expression was associated with a low or absent proliferative response of allogeneic and autologous T cells upon stimulation with tumour cells. In order to investigate the role of B7-1 and B7-2, the human RCC cell line, MZ1257RC, which expresses normal levels of adhesion molecules and major histocompatibility complex (MHC) class I surface antigens, was transfected with B7-1 and B7-2 expression vectors, respectively. The B7-1-and B7-2-transduced MZ1257RC cells were potent stimulators of allogeneic and autologous T-cell proliferation. B7-2 transfectants were approximately two-to threefold more effective in the induction of primary T-cell activation than B7-1-transduced cells. Interleukin (IL)-12 synergized with the B7/CD28 interaction to enhance allogeneic T-cell proliferation, independently of the B7 molecule transduced. In contrast, IL-2 only co-operatively increased T-cell activation in the presence of B7-2. Our results suggest the following: first, that co-stimulatory molecules are required for efficient T-cell responses directed against RCC; second, that B7-2 appears to be a more potent stimulator of tumour immunity as compared to B7-1; and third, that B7 molecules selectively co-operate with different T-cell stimulatory cytokines. The different activity of B7-1 and B7-2 molecules on the immunogenicity of RCC will have implications for the development and optimization of RCC-specific cancer vaccines.

B7‐1 and B7‐2 act differentially in the induction of a T cell response: Their impact for a HLA‐matched and HLA‐mismatched anti‐tumor immunotherapy

“…21 MZ1257RC cells moreover display properties that support their use in the development of an allogeneic vaccine for RCC patients. 8 Upon stable transfection of the B7-negative MZ1257RC cells with the B7-1 and B7-2 expression vectors a number of transfectants expressing different levels of B7 molecules on the cell surface were generated. 8 The levels of B7 on the cell surface of transfectants was determined by measuring the antibody capacity followed by the calculation of the number of B7 molecules/cell.…”

“…In addition, the expression of costimulatory and adhesion molecules were not altered in the B7-expressing cell clones as it has been already shown for B7-transduced bulk cultures. 8 To determine the role of B7 expression on RCC cells, the B7-transfected and the respective control cells were subjected to mixed lymphocyte tumor cell (MLTC) assays. Both quiescent and OKT3 mAb plus IL-2 pre-activated peripheral blood T cells obtained from HLA Class I-matched and HLA Class I-mismatched healthy donors were co-cultured individually with the MZ1257RC cell clones.…”

“…[1][2][3][4] One approach in immunotherapy to eliminate malignant cells is based on transducing tumor cells with either B7-1 or B7-2 to increase their immunogenicity that results in the enhanced generation of tumor-specific, cytotoxic T lymphocytes (CTL). [6][7][8] Upon immunization with tumor cells grafted with B7-1 or B7-2 alone or in addition to MHC Class I molecules or cytokines, mice develop a cell-mediated, specific immune response resulting in tumor rejection, protection against challenge with unmodified tumor cells and induction of a long-term immunologic memory. [9][10][11] Expression of B7-1 or B7-2 in renal cell carcinoma (RCC) cells induces T cell activation and expansion of tumor specific CTL.…”

“…[9][10][11] Expression of B7-1 or B7-2 in renal cell carcinoma (RCC) cells induces T cell activation and expansion of tumor specific CTL. 8,[12][13][14] Due to technical difficulties and high costs in the preparation of autologous vaccines, efforts were undertaken to implement allogeneic tumor cell vaccines. 15 Although RCC is a highly immunogenic tumor 16 and T cells with MHC Class I-restricted recognition of RCC cells were repeatedly isolated, 17,18 only a limited number of RCCassociated antigens has been defined including HER-2/neu, telomerase, G250 and survivin.…”

“…21,22 The implementation of genetically modified tumor cells as vaccines engineered to express T cell co-stimulatory molecules, such as B7-1 or B7-2, has the advantage to generate both CD8 1 and CD4 1 T cell responses. 8,12,13 The impact of B7-1 and B7-2 in activating MHC Class I-matched and mismatched T cells remains unresolved. The analyses we described were designed to determine in a well-controlled in vitro system whether the level of co-stimulatory molecules quantitatively affects particular T cell effector functions and whether the T cell response is modulated by the HLA Class I compatibility of the stimulator cell.…”