Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; California Institute for Biomedical Research, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA.
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cell Chem Biol. 2021 Feb 18;28(2):158-168.e5. doi: 10.1016/j.chembiol.2020.10.005. Epub 2020 Oct 27.
Cancer immunotherapies, including immune checkpoint blockade, have the potential to significantly impact treatments for diverse tumor types. At present, 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. These findings provide further rationale to explore HSP90 inhibitors as part of combination immunotherapies for the treatment of cancer.
癌症免疫疗法，包括免疫检查点阻断，有可能显著影响多种肿瘤类型的治疗。目前，应答失败和免疫相关不良事件仍然是重大问题，通过优化联合治疗可以解决这些问题。通过对大约 20 万个化合物进行基于细胞的化学筛选，我们发现 HSP90 抑制剂通过一种似乎涉及调节主转录调节剂（即 STAT-3 和 c-Myc）的机制，强力降低 PD-L1 表面表达。有趣的是，HSP90 抑制剂也被发现调节其他检查点蛋白（即 PD-L2）的表面表达。在 MC-38 同源小鼠肿瘤模型中，发现 HSP90 抑制显著降低了分离的活肿瘤细胞上 PD-L1 的表面表达，与最近的发现一致，发现它增加了肿瘤微环境中激活的 CD8+T 细胞的数量。这些发现为探索 HSP90 抑制剂作为癌症治疗联合免疫疗法的一部分提供了更多的依据。
