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Abstract：
BACKGROUND: The CDK4/6 inhibitor abemaciclib is an FDA-approved agent and induces T-cell-mediated immunity. Previously, we confirmed the therapeutic potential of abemaciclib on mismatch repair-deficient (dMMR) tumors in mice. Here, we applied a prophylactic administration/dosage setting using two preclinical mouse models of dMMR-driven cancer.
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.
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.
摘要：
背景：CDK4/6抑制剂abemaciclib是FDA批准的药物，可诱导T细胞介导的免疫。以前,我们证实了abemaciclib对小鼠错配修复缺陷(dMMR)肿瘤的治疗潜力.这里,我们使用两种dMMR驱动癌症的临床前小鼠模型进行预防性给药/剂量设定.
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。
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。
