Tumor immunosurveillance plays a crucial role in cancer prevention. Transplant recipients have a 3 to 4 times higher risk of developing skin cancer than the general population, often with multiple aggressive tumors, even in sun-protected areas. They also show a reversal of the ratio of squamous to basal cell carcinomas seen in the general population, from 1:4 to 4:1. Long-term immunosuppressive therapy likely plays a major role in making transplant recipients more susceptible to developing tumors. We reasoned that immune cell numbers might be different in transplant vs nontransplant patients with skin cancer. We examined frequencies of adaptive and innate immune cells in lesions of cutaneous squamous cell carcinoma (SCC) from both patient populations and detected no differences. We therefore hypothesized that the function of innate immune cells might be compromised in transplant recipients, leading to impaired tumor immunosurveillance. We designed an in vitro model to investigate functional differences between macrophages (MACs) and dendritic cells (DCs) in response to SCC. Tumor cells induced release of both interleukin-12 (IL-12) and tumor necrosis factor (TNF)-α from innate immune cells, although IL-12 production was higher in DCs than in MACs. Conversely, TNF-α production was higher in MACs than in DCs. Vascular endothelial growth factor (VEGF), a potent angiogenic factor and an immunosuppressive cytokine, was produced spontaneously and abundantly by tumor cells. DCs exposed to SCC inhibited VEGF production by ≈ 35%, whereas MACs had little effect (only 8.6% decrease). Angiogenesis and immunosuppression are the main mechanisms by which tumors grow and metastasize. Therefore, DCs may play a critical role in anti-tumor immunity by releasing IL-12 and inhibiting VEGF expression by tumor cells, while TNF-α production by MACs may increase VEGF, promoting tumor neovascularization and growth. It is possible that immunosuppressive therapy in transplant patients may impair the immunosurveillance function of DCs and other innate immune cells.
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