TNF autovaccination induces self anti-TNF antibodies and inhibits metastasis in a murine melanoma model

Abstract

TNF is a proinflammatory cytokine involved in the pathogenesis of chronic inflammatory diseases, but also in metastasis in certain types of cancer. In terms of therapy, TNF is targeted by anti-TNF neutralising monoclonal antibodies or soluble TNF receptors. Recently, a novel strategy based on the generation of self anti-TNF antibodies (TNF autovaccination) has been developed. We have previously shown that TNF autovaccination successfully generates high anti-TNF antibody titres, blocks TNF and ameliorates collagen-induced arthritis in DBA/1 mice. In this study, we examined the ability of TNF autovaccination to generate anti-TNF antibody titres and block metastasis in the murine B16F10 melanoma model. We found that immunisation of C57BL/6 mice with TNF autovaccine produces a 100-fold antibody response to TNF compared to immunisation with phosphate-buffered saline vehicle control and significantly reduces both the number (Po0.01) and size of metastases (Po0.01) of B16F10 melanoma cells. This effect is also observed when an anti-TNF neutralising monoclonal antibody is administered, confirming the essential role TNF plays in metastasis in this model. This study suggests that TNF autovaccination is a cheaper and highly efficient alternative that can block TNF and reduce metastasis in vivo and trials with TNF autovaccination are already underway in patients with metastatic cancer.

Blocking Tumor Necrosis Factor α Enhances CD8 T-cell–Dependent Immunity in Experimental Melanoma

“…Vaccination toward TNF triggers self anti-TNF antibodies and inhibits lung invasion of intravenously injected B16 melanoma cells (14). Similar data have been obtained by injecting anti-TNF-neutralizing antibodies (14) or soluble TNF-R1 (15), indicating that TNF blockade may represent a useful strategy to prevent melanoma metastasis. A recent study showed that TNF deficiency can delay tumor growth in a spontaneous mouse model of BRAF V600E melanoma (16).…”

“…Moreover, lung invasion of intravenously injected B16 melanoma cells is decreased in TNF À/À and TNF-R2 À/À mice, indicating that TNF likely enhances melanoma dissemination in a TNF-R2-dependent manner (13). Vaccination toward TNF triggers self anti-TNF antibodies and inhibits lung invasion of intravenously injected B16 melanoma cells (14). Similar data have been obtained by injecting anti-TNF-neutralizing antibodies (14) or soluble TNF-R1 (15), indicating that TNF blockade may represent a useful strategy to prevent melanoma metastasis.…”

The controversial role of TNF in melanoma

“…In melanoma, preclinical models have shown that TNF can induce cell invasion 2 and angiotropism, 3 thus increasing the likelihood of intravasation and hematogenous dissemination; dedifferentiation, and thereby impaired sensitivity to melanocyte-differentiation antigen (MDA)-directed CD8 C immune responses; 4 trigger effector CD8 C T cell death impairing accumulation of CD8 C T cells in the tumor microenvironment. 5 Importantly, TNF inhibition prevents lung metastatization in animal models 6 and, in contrast to earlier reports, it is now demonstrated that chronic treatment with TNF inhibitors does not increase the risk of developing melanoma in human subjects. 7 Our recent studies add additional insights to the puzzling roles of TNF in cancer, pointing out tumor-specific CD4 C T cells as one major source of TNF in the tumor microenvironment of metastatic melanoma in humans driven by tumor MHC class II expression.…”

Tumor necrosis factor, cancer and anticancer therapy

“…More recently, TNF autovaccination has been successfully tested in the murine B16F10 melanoma model to inhibit the metastatization process in vivo [94]. Other investigators used TNF-R1 À/À mice to show that endogenous TNF is crucial for promoting liver metastasis after intrasplenic administration of a colonic adenocarcinoma cell line [95]: more than 90% of wild-type mice develop liver metastases compared with less than 50% of TNF-R1 À/À mice; the difference in metastatic behavior is associated with increased VCAM-1 expression in the livers of wild-type animals, which is instead significantly attenuated in TNF-R1 À/À mice.…”