Combination Immunotherapy of Melanoma by inhibiting HSP90 and targeting its client proteins. (TUM7P.934)

Abstract

Abstract HSP90 plays a major role in human melanoma progression, by facilitating the over expression of its client proteins, many of which provide growth, survival and migratory advantages to tumor cells and support a pro-angiogenic tumor microenvironment. HSP90-mediated stabilization also limits the proteasome-dependent processing of client proteins and the subsequent presentation of derivative peptides in tumor cell-associated MHC class I complexes which is required for effective host CD8+ T cell recognition of melanoma cells. When considered in the combination of active vaccination, inhibiting HSP90 function might serve as a highly effective anti-tumor therapy. As a consequence, we analyzed the anti-tumor impact of a range of clinically-relevant HSP90 inhibitors (HSP90i; i.e. NVP-AUY922, STA9090, 17-DMAG, Novobiocin) on client protein expression in vitro (human and murine melanoma cell lines) and in vivo (s.c. B16 tumors established in syngenic C57BL/6 mice). We observed that HSP90i promote the proteasome-dependent (i.e. blocked by inhibitors PS-341 and MG-132) degradation of a range of client proteins. We have also identified H-2Kb/Db-presented peptide epitopes derived from these client proteins that may be recognized by Type-1 CD8+ T cells after specific vaccination. We are currently investigating the capacity of NVP-AUY922 and STA9090 to therapeutically sensitize established melanomas to client protein-specific CD8+ T cells in combination therapy approaches.