Combination immunotherapy targeting HSP90 DNA repair client proteins overexpressed in melanoma

摘要

DNA repair protein (DNA-RP) overexpression in tumor cells 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. This overexpression of DNA-RP in a cancer-stage associated manner has also been correlated to chemotherapy resistance and poor overall prognosis. Hence, HSP90 inhibitors (HSP90i) have been heralded as cotherapy agents for cancer patients that have developed resistance to first-line treatments such as temozolomide (TMZ). Under conditions in which HSP90 function is blocked by HSP90i, HSP90 client proteins rapidly become polyubiquinated and undergo cytosolic degradation, resulting in sensitization of cancer cells to chemotherapy. We observed that HSP90i promote the proteasome-dependent degradation of a range of DNA repair client proteins, from which, we were able to define nine H-2Kb/Db-presented peptide epitopes that could be recognized by Type-1 CD8+ T cells after specific vaccination. When combined with an adoptive cell therapy (ACT) using anti-DNA-RP CD8+ T cells, HSP90i-cotreatment yielded superior anti-tumor efficacy against TMZ-resistant B16 melanomas established in the dermis of syngenic C57BL/6 mice.udInnovation. This is the first study to focus on the use of HSP90i to conditionally promote the degradation and subsequent presentation of DNA-RP-derived peptides in MHC class I complexes, allowing for improved recognition of chemotherapy-refractory tumor cells by the adaptive (T cell) immune system in vitro and in vivo.udPublic health significance. Melanoma is the deadliest form of skin cancer, with increasing incidence worldwide. This study defines a novel approach that may be translated into the clinic for the treatment of patients with advanced-stage melanomas or alternate chemotherapy-resistant forms of cancer. This approach could be readily combined with a range of synergistic immunotherapies as a novel first- or second-line treatment option for patients that have previously developed (genotoxic or targeted) therapy-specific resistance.