Expression of Co-Stimulatory Molecules by Tumor Cells Decreases Tumorigenicity but May Also Reduce Systemic Antitumor Immunity

Abstract

Many tumor cells do not express co-stimulatory molecules, and this may account, in part, for their poor ability to stimulate T cells directly. One strategy to enhance immune recognition would be to express such molecules on the tumor cell. Here, we show that expression of a member of the B7 family of co-stimulatory molecules by CMT93 murine colorectal tumor or 1735 murine melanoma cells resulted in a local antitumor response in immunocompetent mice. The antitumor effect was diminished in athymic nude mice, indicating that T cells played an important part in this response. The ability of the B7-expressing tumor cells to generate systemic protective immunity was investigated by excision of tumors that developed from the initial inoculation followed by rechallenge with parental tumor cells. CMT93 is a poorly immunogenic tumor and no significant systemic immunity was elicited by the expression of B7-1 in these cells. 1735 melanoma is a mildly immunogenic tumor. Unexpectedly, the systemic immunity obtained with 1735 tumors expressing B7-1 or B7-2 was weaker than that generated by parental 1735 cells (p < 0.001, stratified logrank test), even when coexpression of interferon-gamma in the B7-1 cells produced high levels of surface MHC class I expression. These results suggest that some caution is appropriate when considering the use of these molecules in the gene therapy of cancer.

Tumour cell expression of B7 costimulatory molecules and interleukin-12 or granulocyte–macrophage colony-stimulating factor induces a local antitumour response and may generate systemic protective immunity

“…These mice showed a significantly increased level of protection compared with mice which had been given parental CMT93 cells initially and had tumours that required excision ( Figure 5) (P Ͻ 0.02, stratified log rank test). In the group which had received a primary inoculation of CMT93 B7-1 cells, there was a tendency to improved protection compared with mice which had primary parental tumours but, consistent with our previous findings, 20 analysis of data from independent repeated experiments failed to indicate that this increase was significant. Similarly, mice which had been injected initially with CMT93 IL-12 cells (not coexpressing B7-1) also showed a trend to enhanced protection, but this did not reach a level of significance.…”

“…18,19 CMT93 murine colorectal tumour is of relatively low intrinsic immunogenicity and previously we demonstrated that expression of B7-1 prevented the growth of the primary tumour, but did not produce a significant increase in the level of systemic immunity, relative to that evoked by the parental tumour. 20 Conversely, expression of B7-1 or B7-2 in another tumour, K1735 murine melanoma, a moderately immunogenic tumour, resulted in retarded growth of the primary tumour, but the systemic immunity elicited was weaker than that generated by the parental tumour. 20 Recently, the ability of B7-expressing tumours to elicit systemic immunity was suggested to be dependent not only on direct antigen presentation to T cells by tumour cells, but also on crosspriming of T cells by host professional APCs.…”

“…20 Conversely, expression of B7-1 or B7-2 in another tumour, K1735 murine melanoma, a moderately immunogenic tumour, resulted in retarded growth of the primary tumour, but the systemic immunity elicited was weaker than that generated by the parental tumour. 20 Recently, the ability of B7-expressing tumours to elicit systemic immunity was suggested to be dependent not only on direct antigen presentation to T cells by tumour cells, but also on crosspriming of T cells by host professional APCs. 21,22 Among possible mechanisms by which the latter route of T cell activation may occur is the suggestion that B7 may activate natural killer cells that then lyse tumour cells, thereby increasing the availability of tumour antigens for uptake by professional APCs.…”

B7.1 expression eliminates tumor resistance to IL-12 gene therapy

“…Thus, attempts to enhance tumor immunogenicity have included transfection of tumor cells with cDNA for the B7.1 costimulatory molecule. Several studies report a decrease in tumorigenicity following transfection of tumors with B7.1 7,28 , whereas others have described progressive growth of B7.1 ( + ) tumors. 6,35 These conflicting results may have two explanations.…”

“…Construction of B7.1 ( + ) tumor vaccines in some models has resulted in protection against subsequent wild -type tumor challenge. 7,12,28 Unfortunately, in a clinical model, the presence of a pre -existing tumor burden makes this approach less attractive and a direct treatment model more appealing. B7.1 is one of two known ligands for the CD28 and CTLA -4 receptors on immune effector cells.…”