Blockade of IL-1α and IL-1β signaling by the anti-IL1RAP antibody nadunolimab (CAN04) mediates synergistic anti-tumor efficacy with chemotherapy
Blockade of IL-1α and IL-1β signaling by the anti-IL1RAP antibody nadunolimab (CAN04) mediates synergistic anti-tumor efficacy with chemotherapy
复制标题
抗 IL1RAP 抗体 nadunolimab (CAN04) 阻断 IL-1α 和 IL-1β 信号传导可介导与化疗的协同抗肿瘤功效
DOI：
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
D. Liberg
中科院分区：
文献类型：
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作者：
Camilla Rydberg Millrud;Adnan Deronic;C. Grönberg;Elin Jaensson Gyllenbäck;K. Wachenfeldt;G. Forsberg;D. Liberg
IL-1α和IL-1β都参与了肿瘤生物学的多个方面，包括肿瘤的发生、发展、转移，以及对各种治疗的耐药。IL-1α可以起到警报器的作用，发出细胞应激信号，并诱导下游事件，包括产生IL-1β，以放大信号。IL-1α和IL-1β均通过同一受体复合体IL-1R1-IL1RAP发挥作用，介导信号转导。IL1RAP在肿瘤细胞和肿瘤微环境中通过CAF、巨噬细胞和血管内皮细胞表达。抗IL1RAP抗体Nadunolimab(CAN04)可同时抑制IL-1α和IL-1β信号转导，诱导表达IL1RAP的肿瘤细胞发生ADCC。由于IL-1α和IL-1β均介导化疗耐药，因此本研究的目的是探讨那度单抗与化疗的潜在协同作用。除了体外细胞系实验外，还使用了非小细胞肺癌PDX模型LU2503和同基因MC38模型。我们发现化疗可诱导肿瘤细胞表达和释放IL-1α，并在肿瘤间质中产生IL-1β转换酶。IL-1α还可作用于基质细胞，进一步诱导IL-1β的分泌，这种作用可被那度单抗阻断。Nadunolimab及其替代抗体与基于铂和非铂的化疗具有协同作用，可以诱导强大的抗肿瘤作用，而仅用抗IL-1β抗体阻断IL-1β信号并不能达到这一效果。总之，用Nadunolimab阻断IL1RAP可降低IL-1诱导的肿瘤化疗耐药性。
IL-1α and IL-1β are both involved in several aspects of tumor biology, including tumor initiation, progression, metastasis, and not least in resistance to various therapies. IL-1α can function as an alarmin to signal cellular stress, and acts to induce downstream events, including production of IL-1β, to amplify the signal. Both IL-1α and IL-1β act through the same receptor complex, IL-1R1-IL1RAP, to mediate signal transduction. IL1RAP is expressed on tumor cells and in the tumor microenvironment by for example CAF, macrophages and endothelial cells. The anti-IL1RAP antibody nadunolimab (CAN04) inhibits both IL-1α and IL-1β signaling and induces ADCC of IL1RAP-expressing tumor cells. As both IL-1α and IL-1β mediate chemoresistance, the aim of this study was to explore the potential synergy between nadunolimab and chemotherapy. This was performed using the NSCLC PDX model LU2503 and the syngeneic MC38 model, in addition to in vitro cell line experiments. We show that chemotherapy induces expression and release of IL-1α from tumor cells and production of IL-1β-converting enzyme, ICE, in the tumor stroma. IL-1α is also demonstrated to act on stromal cells to further induce the secretion of IL-1β, an effect disrupted by nadunolimab. Nadunolimab, and its surrogate antibody, synergize with platinum-based as well as non-platinum-based chemotherapy to induce potent anti-tumor effects, while blockade of only IL-1β signaling by anti-IL-1β antibody does not achieve this effect. In conclusion, blockade of IL1RAP with nadunolimab reduces IL-1-induced chemoresistance of tumors.
DOI：
10.1152/ajprenal.1996.270.4.f700
发表时间：
1996-04-01
期刊：
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL FLUID AND ELECTROLYTE PHYSIOLOGY
影响因子：
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作者：
Lieberthal, W;Triaca, V;Levine, J
通讯作者：
Levine, J