Soluble tumor necrosis factor receptor type I enhances tumor development and persistence in vivo.

Secretion of human soluble tumor necrosis factor receptor type I (sTNFRI) by the mouse fibrosarcoma cell line, L929, previously has been demonstrated to confer resistance to in vitro lysis by TNF and to LAK- and CTL-mediated cytolysis. These findings suggest that, in vivo, sTNFRI contributes to tumor survival by inhibiting these immunologic mechanisms. To evaluate this hypothesis, we compared the growth of sTNFRI-secreting L929 cells with that of the unmodified parental fibrosarcoma in an in vivo mouse transplantation model. Secretion of sTNFRI by L929 cells markedly enhanced their tumorigenicity and persistence in syngeneic recipients. This benefit was abrogated by sTNFRI-neutralizing antibodies induced by immunization prior to tumor challenge. These data demonstrate that sTNFRI directly influences tumor formation and persistence in vivo and suggest the selective removal and/or inactivation of sTNFRI as a promising new avenue for cancer immunotherapy.

Multifaceted inhibition of anti-tumour immune mechanisms by soluble tumour necrosis factor receptor type I.

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 immunity. 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 immune 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 immunological 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 immunotherapy.