Collagen-binding IL-12 enhances tumour inflammation and drives the complete remission of established immunologically cold mouse tumours
Collagen-binding IL-12 enhances tumour inflammation and drives the complete remission of established immunologically cold mouse tumours
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DOI：
10.1038/s41551-020-0549-2
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发表时间：
2020-04-13
影响因子：
28.1
通讯作者：
Hubbell, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Mansurov, Aslan;Ishihara, Jun;Hubbell, Jeffrey A.
检查点抑制剂（CPI）免疫疗法取得了显著的临床成功，但其在“免疫冷”肿瘤中的疗效一直不高。白细胞介素-12 （IL-12）是一种强大的细胞因子，可激活免疫系统的先天和适应性臂；然而，IL-12的施用与免疫相关的不良事件有关。本研究表明，在携带侵袭性小鼠肿瘤的小鼠中，静脉注射与IL-12融合的胶原结合结构域（CBD-IL-12）后，由于无序的肿瘤血管中暴露的胶原，CBD-IL-12在肿瘤基质中积累。与未修饰的IL-12相比，CBD-IL-12诱导肿瘤内持续的干扰素γ水平，大大降低了其全身水平和器官损伤，并提供了优越的抗癌功效，引起cpi无反应的乳腺肿瘤完全消退。此外，在基因工程小鼠黑色素瘤模型中，CBD-IL-12与CPI有效协同消除大的已建立的黑色素瘤，诱导抗原特异性免疫记忆并控制肿瘤生长。CBD-IL-12可能增强CPI对免疫冷肿瘤的免疫治疗。将一种胶原结合白介素-12制剂静脉注射到患有已建立的免疫冷小鼠肿瘤的小鼠体内，可显著缓解肿瘤，特别是与检查点抑制剂免疫疗法联合使用时。
Checkpoint-inhibitor (CPI) immunotherapy has achieved remarkable clinical success, yet its efficacy in 'immunologically cold' tumours has been modest. Interleukin-12 (IL-12) is a powerful cytokine that activates the innate and adaptive arms of the immune system; however, the administration of IL-12 has been associated with immune-related adverse events. Here we show that, after intravenous administration of a collagen-binding domain fused to IL-12 (CBD-IL-12) in mice bearing aggressive mouse tumours, CBD-IL-12 accumulates in the tumour stroma due to exposed collagen in the disordered tumour vasculature. In comparison with the administration of unmodified IL-12, CBD-IL-12 induced sustained intratumoural levels of interferon-gamma, substantially reduced its systemic levels as well as organ damage and provided superior anticancer efficacy, eliciting complete regression of CPI-unresponsive breast tumours. Furthermore, CBD-IL-12 potently synergized with CPI to eradicate large established melanomas, induced antigen-specific immunological memory and controlled tumour growth in a genetically engineered mouse model of melanoma. CBD-IL-12 may potentiate CPI immunotherapy for immunologically cold tumours.A collagen-binding interleukin-12 formulation intravenously injected into mice bearing established immunologically cold mouse tumours led to marked tumour remission, particularly when combined with checkpoint-inhibitor immunotherapy.