Abstract LB-225: Combination immunotherapy targeting HSP90 DNA-repair client proteins overexpressed in chemotherapy-resistant melanoma

Abstract

DNA repair protein (DNA-RP) overexpression has been reported to involve post-translational protein stabilization mediated by the molecular chaperone heat shock protein 90(HSP90), thereby preventing proteasome-dependent degradation of these HSP90 “client” proteins. Overexpression of DNA-RP in a disease-stage associated manner has also been correlated to chemo resistance and poor overall prognosis. Hence, HSP90 inhibitors (HSP90i) have been heralded as co-therapy agents for cancer patients that have developed resistance to first-line treatments such as temozolomide (TMZ). In the presence of HSP90i, HSP90 client proteins rapidly become (poly)ubiquinated and undergo degradation resulting in the improved sensitization of cancer cells to chemo therapy. We observed that HSP90i promote the proteasome-dependent degradation of a broad range of DNA-repair client proteins. We have also identified 9 H-2Kb/Db-presented peptide epitopes derived from DNA-RPs that may be recognized by Type-1 CD8+ T cells after specific vaccination. When combined with adoptive cell therapy using DNA-RP-specific CD8+ T cells, HSP90i cotreatment yielded superior anti-tumor efficacy against established TMZ-resistant B16 tumors in C57BL/6 mice. Citation Format: Subhara Raveendran, Ronald Fecek, Cara Donahue Carey, Walter J. Storkus. Combination immunotherapy targeting HSP90 DNA-repair client proteins overexpressed in chemotherapy-resistant melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-225.