白蘑菇处理后前列腺癌小鼠模型和患者中髓源性抑制细胞的减少。
Reduction of myeloid-derived suppressor cells in prostate cancer murine models and patients following white button mushroom treatment.
机构信息
Department of Cancer Biology & Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, California, USA.
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, California, USA.
出版信息
Clin Transl Med. 2024 Oct;14(10):e70048. doi: 10.1002/ctm2.70048.
BACKGROUND
In a previously reported Phase I trial, we observed therapy-associated declines in circulating myeloid-derived suppressor cells (MDSCs) with the administration of white button mushroom (WBM) tablets in prostate cancer (PCa) patients. These observations led us to hypothesise that WBM could mitigate PCa progression by suppressing MDSCs.
METHODS
We performed bidirectional translational research to examine the immunomodulatory effects of WBM consumption in both syngeneic murine PCa models and patients with PCa participating in an ongoing randomised Phase II trial (NCT04519879).
RESULTS
In murine models, WBM treatment significantly suppressed tumour growth with a reduction in both the number and function of MDSCs, which in turn promoted antitumour immune responses mediated by T cells and natural killer (NK) cells. In patients, after consumption of WBM tablets for 3 months, we observed a decline in circulating polymorphonuclear MDSCs (PMN-MDSCs), along with an increase in cytotoxic CD8 T and NK cells. Furthermore, single immune cell profiling of peripheral blood from WBM-treated patients showed suppressed STAT3/IRF1 and TGFβ signalling in circulating PMN-MDSCs. Subclusters of PMN-MDSCs presented transcriptional profiles associated with responsiveness to fungi, neutrophil chemotaxis, leukocyte aggregation, and regulation of inflammatory response. Finally, in mouse models of PCa, we found that WBM consumption enhanced the anticancer activity of anti-PD-1 antibodies, indicating that WBM may be used as an adjuvant therapy with immune checkpoint inhibitors.
CONCLUSION
Our results from PCa murine models and patients provide mechanistic insights into the immunomodulatory effects of WBM and provide a scientific foundation for WBM as a nutraceutical intervention to delay or prevent PCa progression.
HIGHLIGHTS
White button mushroom (WBM) treatment resulted in a reduction in pro-tumoural MDSCs, notably polymorphonuclear MDSCs (PMN-MDSCs), along with activation of anti-tumoural T and NK cells. Human single immune cell gene expression profiling shed light on the molecular alterations induced by WBM, specifically on PMN-MDSCs. A proof-of-concept study combining WBM with PD-1 blockade in murine models revealed an additive effect on tumour regression and survival outcomes, highlighting the clinical relevance of WBM in cancer management.
背景
在之前报道的 I 期临床试验中，我们观察到在前列腺癌（PCa）患者中使用白蘑菇（WBM）片治疗后，循环髓系来源的抑制细胞（MDSCs）下降。这些观察结果使我们假设 WBM 通过抑制 MDSCs 来减轻 PCa 的进展。
方法
我们进行了双向转化研究，以检查 WBM 消耗对同种异体小鼠 PCa 模型和正在进行的随机 II 期试验（NCT04519879）中参与的 PCa 患者的免疫调节作用。
结果
在小鼠模型中，WBM 治疗显著抑制肿瘤生长，减少 MDSCs 的数量和功能，从而促进 T 细胞和自然杀伤（NK）细胞介导的抗肿瘤免疫反应。在患者中，WBM 片治疗 3 个月后，我们观察到循环多形核 MDSCs（PMN-MDSCs）下降，同时细胞毒性 CD8 T 和 NK 细胞增加。此外，WBM 治疗患者外周血的单个免疫细胞分析显示，循环 PMN-MDSCs 中的 STAT3/IRF1 和 TGFβ 信号受到抑制。PMN-MDSCs 的亚群呈现与真菌反应性、中性粒细胞趋化性、白细胞聚集和炎症反应调节相关的转录谱。最后，在 PCa 小鼠模型中，我们发现 WBM 消耗增强了抗 PD-1 抗体的抗癌活性，表明 WBM 可用作免疫检查点抑制剂的辅助治疗。
结论
我们从 PCa 小鼠模型和患者中获得的结果提供了 WBM 免疫调节作用的机制见解，并为 WBM 作为延缓或预防 PCa 进展的营养干预措施提供了科学依据。
重点
白蘑菇（WBM）治疗导致促肿瘤 MDSCs，特别是多形核 MDSCs（PMN-MDSCs）减少，同时激活抗肿瘤 T 和 NK 细胞。人类单个免疫细胞基因表达谱分析揭示了 WBM 诱导的分子改变，特别是对 PMN-MDSCs 的改变。结合 WBM 与 PD-1 阻断在小鼠模型中的一项概念验证研究显示对肿瘤消退和生存结果具有附加效应，突出了 WBM 在癌症管理中的临床相关性。
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