Multifaceted inhibition of anti‐tumour imm_une mechanisms by soluble tumour necrosis factor receptor type I

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Abstract
Soluble tumour necrosis factor receptor type I (sTNFRI) is a potent inhibitor of TNF with the potential to suppress a variety of effector mechanisms important in tumour imm_unity. That sTNFRI influences tumour survival in vivo is suggested by results from human clinical trials of Ultrapheresis®, an experimental extracorporeal treatment for cancer. While the considerable clinical benefit provided by Ultrapheresis® is correlated with the removal of plasma sTNFRI, there is no direct evidence that sTNFRI inhibits imm_une mechanisms which mediate tumour cell elimination. To evaluate formally the ability of sTNFRI to inhibit these mechanisms, we have engineered sTNFRI production into the TNF‐sensitive murine fibrosarcoma cell line, L929. Soluble TNFRI‐secreting L929 cells display increased resistance to direct lysis by TNF, and to lysis by syngeneic lymphokine‐activated killer cells and cytotoxic T cells. These findings confirm the suggestion that sTNFRI inhibits imm_unological mechanisms important in tumour cell eradication, and further support a role for sTNFRI in tumour survival in vivo. In addition, these observations suggest the development of methods for more specific removal and/or inactivation of sTNFRI as promising new avenues for cancer imm_unotherapy.