METHODS: Mlh1-/- and Msh2loxP/loxP mice received repeated prophylactic applications of abemaciclib mesylate (75 mg/kg bw, per oral) as monotherapy or were left untreated. Blood phenotyping and multiplex cytokine measurements were performed regularly. The tumor microenvironment was evaluated by immunofluorescence and Nanostring-based gene expression profiling. Numbers, size and immune composition and activity of extracellular vesicles (EVs) were studied at the endpoint.
RESULTS: Prophylactic abemaciclib-administration delayed tumor development and significantly prolonged overall survival in both mouse strains (Mlh1-/-: 50.0 wks vs. control: 33.9 wks; Msh2loxP/loxP;TgTg(Vil1-cre: 58.4 wks vs. control 44.4 wks). In Mlh1-/- mice, pro-inflammatory cytokines (IL-2, IL-6) significantly increased, whereas IL-10 and IL-17A decreased. Circulating and splenic exhausted and regulatory T cell numbers were significantly lower in the abemaciclib groups. Deeper analysis of late-onset tumors revealed activation of the Hedgehog and Notch signaling in Mlh1-/- mice, and activation of the MAPK pathway in Msh2loxP/loxP;TgTg(Vil1-cre mice. Still, arising tumors had fewer infiltrating myeloid-derived suppressor cells (vs. control). Notably, prophylactic abemaciclib-administration prevented secretion of procoagulant EVs but triggered release of immunomodulatory EVs in Mlh1-/- mice.
CONCLUSIONS: Prophylactic abemaciclib prolongs survival via global immunomodulation. Prophylactic use of abemaciclib should be considered further for individuals with inherited dMMR.
BACKGROUND: This work was supported by grants from the German research foundation [DFG grant number: MA5799/2-2] and the Brigitte und Dr. Konstanze Wegener-Stiftung to CM.
方法:Mlh1-/-和Msh2loxP/loxP小鼠反复预防性应用甲磺酸abemaciclib(75mg/kgbw,每次口服)作为单一疗法或不治疗。定期进行血液表型分析和多重细胞因子测量。通过免疫荧光和基于Nanostring的基因表达谱分析评估肿瘤微环境。Numbers,在终点研究了细胞外囊泡(EV)的大小,免疫组成和活性。
结果:在两种小鼠品系中,预防性给药可延迟肿瘤发展并显着延长总生存期(Mlh1-/-:50.0wksvs.控制:33.9周;Msh2loxP/loxP;TgTg(Vil1-cre:58.4周vs.控制44.4周)。在Mlh1-/-小鼠中,促炎细胞因子(IL-2,IL-6)显着增加,而IL-10和IL-17A降低。在abemaciclib组中,循环和脾衰竭和调节性T细胞数量显着降低。对迟发性肿瘤的深入分析揭示了Mlh1-/-小鼠中Hedgehog和Notch信号的激活,和Msh2loxP/loxP中MAPK途径的激活;TgTg(Vil1-cre小鼠。尽管如此,出现的肿瘤浸润性髓源性抑制细胞较少(与控制)。值得注意的是,在Mlh1-/-小鼠中,预防性给予abemaciclib阻止了促凝血EV的分泌,但引发了免疫调节EV的释放.
结论:预防性abemaciclib通过整体免疫调节延长生存期。对于患有遗传性dMMR的个体,应进一步考虑预防性使用abemaciclib。
背景:这项工作得到了德国研究基金会[DFG资助号:MA5799/2-2]和BrigitteundKonstanzeWegener-Stiftung博士对CM的资助。