Metastatic melanoma is a significant clinical problem with a 5-year survival rate of only 15-20%. Recent approval of new immunotherapies and targeted inhibitors have provided much needed options for these patients, in some cases promoting dramatic disease regressions. In particular, antibody-based therapies that block the PD-1/PD-L1 checkpoint inhibitory pathway have achieved an increased overall response rate in metastatic melanoma, yet durable response rates are reported only around 15%. To improve the overall and durable response rates for advanced-stage melanoma, combined targeted and immune-based therapies are under investigation. Here, we investigated how the natural products called schweinfurthins, which have selective anti-proliferative activity against many cancer types, impact anti-(α)PD-1-mediated immunotherapy of murine melanomas. Two different compounds efficiently reduced the growth of human and murine melanoma cells in vitro and induced plasma membrane surface localization of the ER-resident protein calreticulin in B16.F10 melanoma cells, an indicator of immunogenic cell death. In addition, both compounds improved αPD-1-mediated immunotherapy of established tumors in immunocompetent C57BL/6 mice either by delaying tumor progression or resulting in complete tumor regression. Improved immunotherapy was accomplished following only a 5-day course of schweinfurthin, which was associated with initial tumor regression even in the absence of αPD-1. Schweinfurthin-induced tumor regression required an intact immune system as tumors were unaffected in NOD scid gamma (NSG) mice. These results indicate that schweinfurthins improve αPD-1 therapy, leading to enhanced and durable anti-tumor immunity and support the translation of this novel approach to further improve response rates for metastatic melanoma.

中文翻译：

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Schweinfurthin天然产物可诱导鼠黑色素瘤消退，并与抗PD-1治疗配对以促进持久的肿瘤免疫力。

转移性黑色素瘤是一个重要的临床问题，其5年生存率仅为15-20％。新的免疫疗法和靶向抑制剂的最新批准为这些患者提供了急需的选择，在某些情况下促进了疾病的急剧恶化。特别是，阻断PD-1 / PD-L1检查点抑制途径的基于抗体的疗法在转移性黑色素瘤中已实现了提高的总体缓解率，但据报道持久缓解率仅约15％。为了提高晚期黑色素瘤的总体和持久反应率，正在研究结合靶向和基于免疫的疗法。在这里，我们研究了称为schweinfurthins的天然产物如何对多种类型的癌症具有选择性的抗增殖活性，它们如何影响抗（α）PD-1介导的鼠类黑色素瘤的免疫治疗。两种不同的化合物在体外有效减少了人和鼠黑色素瘤细胞的生长，并诱导了B16.F10黑色素瘤细胞中ER驻留蛋白钙网蛋白的质膜表面定位，这是免疫原性细胞死亡的指标。另外，这两种化合物通过延迟肿瘤进展或导致肿瘤完全消退，改善了具有免疫功能的C57BL / 6小鼠中αPD-1介导的已建立肿瘤的免疫治疗。仅用5天的施维因素治疗就可以改善免疫治疗效果，即使在没有αPD-1的情况下，这也与初始肿瘤消退有关。Schweinfurthin诱导的肿瘤消退需要完整的免疫系统，因为在NOD scidγ（NSG）小鼠中肿瘤不受影响。这些结果表明，schweinfurthins可改善αPD-1治疗，