Abstract 1931: Impact of bortezomib-induced proteasome inhibition in vivo on antitumor T cell responses

Abstract

Abstract Inhibition of cellular proteasome function crucial for protein turn-over is a recent approach to overcome the resistance of tumors to cell death, a major clinical problem. Bortezomib (also known as Velcade/PS-341), a specific and reversible proteasome inhibitor, has been shown to sensitize some mouse and human tumors to apoptosis induced by the TNF-related apoptosis-inducing ligand (TRAIL) or its receptor (DR5) agonist monoclonal antibody (mAb). In established mouse renal cell (Renca) and breast (4T1) tumor models, the administration of DR5 agonist mAb to tumor-bearing mice pre-treated with bortezomib reduced experimental lung metastases. The combination of bortezomib and DR5 agonist mAb also significantly increased long-term survival of mice bearing Renca tumors compared with either agent alone. The therapeutic effects of bortezomib on tumor metastases and survival of tumor-bearing mice occurred in the absence of overt toxicity. However, little is known concerning the effects of bortezomib on specific immune responses. We thus analyzed the effects of proteasome inhibition on anti-tumor T cell responses in vivo. In mice with established Renca-HA tumor expressing influenza virus hemagglutinin (HA) as a surrogate tumor antigen, we evaluated the antigen-specific proliferation of adoptively transferred monoclonal HA-specific MHC class I or II restricted T cells following various schedules of bortezomib administration. No inhibition of T cell proliferation or cytolytic function in vivo was observed following bortezomib treatments. Nor was there any evidence of defective dendritic cell maturation in bortezomib-treated mice. However, a significant decrease in total T cell yield was noted in the tumor-draining LNs of mice treated with bortezomib. Thus, bortezomib-inhibitory effects on T cell responses seem quantitative rather than qualitative. The basis for this decrease in T cell number is under further investigation. The findings imply that, with an appropriate scheduling, it may be possible to combine bortezomib-induced sensitization of tumors to apoptosis with tumor-specific T cell immunotherapy regimens for increased therapeutic benefit in cancer. Funded in part by NCI Contract # N01-CO-12400 and HHSN261200800001E. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1931.