Proteasome inhibition promotes tumor cell apoptosis by exogenous TRAIL without blocking anti-tumor immune effectors in vivo (50.6)

The resistance of tumors to cell death poses a major clinical problem. Bortezomib (Velcade/PS-341), a specific and reversible proteasome inhibitor, sensitized renal (Renca) and mammary (4T1) mouse carcinomas to apoptosis induced by the TNF family ligand TRAIL or its receptor (DR5) agonist antibody. The molecular basis of the tumoritoxicity of the combination of bortezomib and TRAIL seemingly involved amplification of the extrinsic cell death pathway as increased expression of DR5, activation of caspase-8 and -3, and decreased apoptosis inhibitory proteins cFLIP, cIAP-1 and XIAP were observed in bortezomib-treated tumors. In an established tumor setting, anti-DR5 administration to mice pre-treated with bortezomib not only reduced lung metastases of Renca and 4T1 tumors but also significantly increased long-term survival in mice bearing Renca as compared to either agent alone. Encouragingly, no evidence of any overt tissue damage was noted in the treated mice. This provides the first experimental evidence that proteasome inhibition can be combined with DR5 agonist antibody for successful cancer therapy. Moreover, bortezomib administration 24 hours prior to adoptive transfer of T cells did not block their anti-tumor effector function. This suggests that tumor sensitization with bortezomib may also be combined with tumor-specific T cell immunotherapy of cancer. Funded in part by NCI contract N01-CO-12400.