Assay Development and Screening
Cancer immunotherapies, including blockade of the PD-1/PD-L1 immune checkpoint, have demonstrated dramatic efficacy against a diverse set of tumor types. However, response failures and immune-related adverse events remain significant issues, which could be addressed using optimized combination therapies. Through a cell-based chemical screen of ∼200,000 compounds, we identified that HSP90 inhibitors robustly decrease PD-L1 surface expression, through a mechanism that appears to involve the regulation of master transcriptional regulators (i.e., STAT-3 and c-Myc). Interestingly, HSP90 inhibitors were found to also modulate the surface expression of additional checkpoint proteins (i.e., PD-L2). In the MC-38 syngeneic mouse tumor model, HSP90 inhibition was found to dramatically reduce PD-L1 surface expression on isolated live tumor cells and, consistent with recent findings, was found to increase the number of activated CD8+ T cells within the tumor microenvironment. While HSP90 inhibitors have been thoroughly studied in numerous cancer clinical trials, to date they have failed to achieve sufficient efficacy. However, few, if any, of these trials have combined HSP90 inhibition with immunotherapy or considered the PD-L1 status of tumors as a selection criterion for subjects. These findings provide further rationale to explore HSP90 inhibitors as part of combination immunotherapies for the treatment of cancer.