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Type I IFN, Ly6C+ cells, and phagocytes support suppression of peritoneal carcinomatosis elicited by a TLR and CLR agonist combination
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2020-03-18 , DOI: 10.1158/1535-7163.mct-19-0885
Allison M Dyevoich 1 , Karen M Haas 1
Affiliation  

Metastatic cancer involving spread to the peritoneal cavity is referred to as peritoneal carcinomatosis and has a very poor prognosis. Our previous study demonstrated a Toll-like receptor and C-type lectin receptor agonist pairing of monophosphoryl lipid A (MPL) and trehalose-6,6′-dicorynomycolate (TDCM) effectively inhibits tumor growth and ascites development following TA3-Ha and EL4 challenge through a mechanism dependent on B-1a cell–produced natural IgM and complement. In this study, we investigated additional players in the MPL/TDCM-elicited response. MPL/TDCM treatment rapidly increased type I IFN levels in the peritoneal cavity along with myeloid cell numbers, including macrophages and Ly6Chi monocytes. Type I IFN receptor (IFNAR1−/−) mice produced tumor-reactive IgM following MPL/TDCM treatment, but failed to recruit Ly6C+ monocytes and were not afforded protection during tumor challenges. Clodronate liposome depletion of phagocytic cells, as well as targeted depletion of Ly6C+ cells, also ablated MPL/TDCM-induced protection. Cytotoxic mediators known to be produced by these cells were required for effects. TNFα was required for effective TA3-Ha killing and nitric oxide was required for EL4 killing. Collectively, these data reveal a model whereby MPL/TDCM-elicited antitumor effects strongly depend on innate cell responses, with B-1a cell–produced tumor-reactive IgM and complement pairing with myeloid cell–produced cytotoxic mediators to effectively eradicate tumors in the peritoneal cavity.

中文翻译:

I 型 IFN、Ly6C+ 细胞和吞噬细胞支持抑制由 TLR 和 CLR 激动剂组合引起的腹膜癌病

涉及扩散到腹膜腔的转移性癌症被称为腹膜癌病,预后很差。我们之前的研究表明,单磷酰脂质 A (MPL) 和 trehalose-6,6'-dicorynomycolate (TDCM) 的 Toll 样受体和 C 型凝集素受体激动剂配对可有效抑制 TA3-Ha 和 EL4 激发后的肿瘤生长和腹水发展通过依赖于 B-1a 细胞产生的天然 IgM 和补体的机制。在这项研究中,我们调查了 MPL/TDCM 引发的响应中的其他参与者。MPL/TDCM 治疗迅速增加了腹腔中的 I 型干扰素水平以及髓细胞数量,包括巨噬细胞和 Ly6Chi 单核细胞。I 型 IFN 受体 (IFNAR1-/-) 小鼠在 MPL/TDCM 治疗后产生肿瘤反应性 IgM,但未能招募 Ly6C+ 单核细胞,并且在肿瘤攻击期间没有得到保护。吞噬细胞的氯膦酸脂质体消耗,以及 Ly6C+ 细胞的靶向消耗,也消除了 MPL/TDCM 诱导的保护。已知由这些细胞产生的细胞毒性介质是产生效果所必需的。有效杀死 TA3-Ha 需要 TNFα,而杀死 EL4 需要一氧化氮。总的来说,这些数据揭示了一个模型,其中 MPL/TDCM 引发的抗肿瘤作用强烈依赖于先天细胞反应,B-1a 细胞产生的肿瘤反应性 IgM 和补体与骨髓细胞产生的细胞毒性介质配对,以有效根除腹膜肿瘤腔。还消融了 MPL/TDCM 诱导的保护。已知由这些细胞产生的细胞毒性介质是产生效果所必需的。有效杀死 TA3-Ha 需要 TNFα,而杀死 EL4 需要一氧化氮。总的来说,这些数据揭示了一个模型,其中 MPL/TDCM 引发的抗肿瘤作用强烈依赖于先天细胞反应,B-1a 细胞产生的肿瘤反应性 IgM 和补体与骨髓细胞产生的细胞毒性介质配对,以有效根除腹膜肿瘤腔。还消融了 MPL/TDCM 诱导的保护。已知由这些细胞产生的细胞毒性介质是产生效果所必需的。有效杀死 TA3-Ha 需要 TNFα,而杀死 EL4 需要一氧化氮。总的来说,这些数据揭示了一个模型,其中 MPL/TDCM 引发的抗肿瘤作用强烈依赖于先天细胞反应,B-1a 细胞产生的肿瘤反应性 IgM 和补体与骨髓细胞产生的细胞毒性介质配对,以有效根除腹膜肿瘤腔。
更新日期:2020-03-18
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