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Expression of co-stimulatory molecules by tumor cells decreases tumorigenicity but may also reduce systemic antitumor
H Chong1, G Hutchinson, I R Hart
1Imperial Cancer Research Fund Laboratory of Cancer Gene Therapy, Rayne Institute, St. Thomas' Hospital, London, UK.
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.
Insights
Expressing B7 co-stimulatory molecules on tumor cells can create a local antitumor response. However, this approach may not generate systemic immunity and requires caution for cancer gene therapy.
Area of Science:
- Immunology
- Oncology
- Cancer Gene Therapy
Background:
- Tumor cells often lack co-stimulatory molecules, hindering T cell recognition and immune response.
- Enhancing immune recognition by expressing co-stimulatory molecules on tumor cells is a potential cancer therapy strategy.
Purpose of the Study:
- To investigate the impact of B7 co-stimulatory molecule expression on tumor cells for eliciting antitumor responses.
- To evaluate the potential of B7-expressing tumor cells in generating local and systemic protective immunity.
Main Methods:
- Expression of B7 co-stimulatory molecules in CMT93 (colorectal) and 1735 (melanoma) murine tumor cells.
- Assessment of local antitumor response in immunocompetent and athymic nude mice.
- Evaluation of systemic protective immunity through tumor excision and rechallenge experiments.
Main Results:
- B7 expression on tumor cells induced a local antitumor response in immunocompetent mice, dependent on T cells.
- CMT93 tumors expressing B7-1 did not elicit significant systemic immunity.
- Surprisingly, B7-1 or B7-2 expression in 1735 melanoma cells resulted in weaker systemic immunity compared to parental cells.
Conclusions:
- While B7 co-stimulatory molecules can promote local antitumor immunity, their efficacy in generating systemic protective immunity is variable and potentially detrimental.
- Caution is advised when considering B7 family molecules for cancer gene therapy due to unexpected outcomes in systemic immunity.