High-Intensity Focused Ultrasound (HIFU) Triggers Immune Sensitization of Refractory Murine Neuroblastoma to Checkpoint Inhibitor Therapy.
High-Intensity Focused Ultrasound (HIFU) Triggers Immune Sensitization of Refractory Murine Neuroblastoma to Checkpoint Inhibitor Therapy.
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DOI：
10.1158/1078-0432.ccr-19-1604
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发表时间：
2020-03-01
影响因子：
11.5
通讯作者：
Kim, Peter C. W.
中科院分区：
文献类型：
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作者：
Eranki, Avinash;Srinivasan, Priya;Ries, Mario;Kim, AeRang;Lazarski, Christopher A.;Rossi, Christopher T.;Khokhlova, Tatiana D.;Wilson, Emmanuel;Knoblach, Susan M.;Sharma, Karun, V;Wood, Bradford J.;Moonen, Chrit;Sandler, Anthony D.;Kim, Peter C. W.
免疫疗法有望为癌症患者带来前所未有的好处。然而，大多数癌症类型，包括高危神经母细胞瘤，仍然对免疫无反应。高强度聚焦超声(HIFU)是一种非侵入性技术，可以机械分割肿瘤，从免疫上转化为冷肿瘤；冷肿瘤变成有反应的肿瘤；热肿瘤。我们用机械HIFU治疗了先前无反应的、大的、难治的小鼠神经母细胞瘤肿瘤体积的2%，并用流式细胞仪、酶联免疫吸附试验和基因测序评估了系统免疫反应。此外，我们还将其与α、CTLA-4和αPD-L1联合应用，研究其对免疫应答和长期生存的影响。HIFU联合α、CTLA-4和αPD-L1可显著增强抗肿瘤反应，将存活率从0提高到62.5%。HIFU单独引起脾和淋巴结NK细胞的上调以及循环中的IL-2、干扰素-Ɣ和DAMPS，而免疫调节因子如CD4+Foxp3+、IL-10和血管内皮生长因子-A则显著降低。与未治疗组比较，HIFU联合检查点抑制剂治疗后，瘤内CD_4~+、CD_8~+ɑ~+、CD_8~+α~+、CD_(11)c~+细胞、局部淋巴结CD11~+细胞显著升高，循环IL-10明显降低。我们还报告了与单独使用高强度聚焦超声或检查点抑制剂治疗肿瘤(61.1%的存活率，p<；0.0001)相比，使用高强度聚焦超声和检查点抑制剂单侧治疗大的、已建立的双侧肿瘤的小鼠具有显著的非局部性效应。这种联合治疗还可显著诱导CD_4+CD_(44+)和CD_8+α+CD_(44+)+H_(CD62L+)低群体，并具有可转移性，可传递免疫，延缓随后的肿瘤移植。使用HIFU的肿瘤机械分割可以有效地在先前无反应的小鼠神经母细胞瘤模型中诱导免疫敏化，并有望成为一种新的但有效的免疫佐剂方式来克服治疗耐药性。
Immunotherapy promises unprecedented benefits to cancer patients. However, the majority of cancer types, including high-risk neuroblastoma remain immunologically unresponsive. High intensity focused ultrasound (HIFU) is a non-invasive technique that can mechanically fractionate tumors, transforming immunologically “;cold” tumors into responsive “;hot” tumors. We treated <2% of tumor volume in previously unresponsive, large, refractory murine neuroblastoma tumors with mechanical HIFU, and assessed systemic immune response using flow-cytometry, ELISA, and gene sequencing. In addition, we combined this treatment with αCTLA-4 and αPD-L1 to study its effect on the immune response and long-term survival. Combining HIFU with αCTLA-4 and αPD-L1 significantly enhances anti-tumor response, improving survival from 0 to 62.5%. HIFU alone causes upregulation of splenic and lymph node NK cells and circulating IL-2, IFN-Ɣ, and DAMPs, whereas immune regulators like CD4+Foxp3+, IL-10, and VEGF-A are significantly reduced. HIFU combined with checkpoint inhibitors induced significant increases in intratumoral CD4+, CD8ɑ+, and CD8α+CD11c+ cells, CD11c+ in regional lymph nodes, and decrease in circulating IL-10 compared to untreated group. We also report significant abscopal effect following unilateral treatment of mice with large, established bilateral tumors using HIFU and checkpoint inhibitors compared to tumors treated with HIFU or checkpoint inhibitors alone (61.1% survival, p<0.0001). This combination treatment significantly also induces CD4+CD44+hiCD62L+low and, CD8α+CD44+hiCD62L+low population and are adoptively transferable imparting immunity, slowing subsequent de novo tumor engraftment. Mechanical fractionation of tumors using HIFU can effectively induce immune sensitization in a previously unresponsive murine neuroblastoma model, and promises a novel yet efficacious immuno-adjuvant modality to overcome therapeutic resistance.