Combination of ultrasound-based mechanical disruption of tumor with immune checkpoint blockade modifies tumor microenvironment and augments systemic antitumor immunity.
Combination of ultrasound-based mechanical disruption of tumor with immune checkpoint blockade modifies tumor microenvironment and augments systemic antitumor immunity.
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基于超声的肿瘤机械破坏与免疫检查点阻断相结合可改变肿瘤微环境并增强全身性抗肿瘤免疫。
DOI：
10.1136/jitc-2021-003717
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发表时间：
2022-01
影响因子：
10.9
通讯作者：
Osada T
中科院分区：
文献类型：
--
作者：
Abe S;Nagata H;Crosby EJ;Inoue Y;Kaneko K;Liu CX;Yang X;Wang T;Acharya CR;Agarwal P;Snyder J;Gwin W;Morse MA;Zhong P;Lyerly HK;Osada T
尽管采用放疗、化疗和激素疗法等多模式辅助治疗，但大多数手术切除的原发性乳腺癌仍会复发或转移。晚期和远处复发的一个潜在解决方案是增强全身抗肿瘤免疫力，部分通过适当呈递肿瘤抗原，但也通过调节免疫抑制性肿瘤微环境（TME）。我们之前在用新型高强度聚焦超声（HIFU）、机械高强度聚焦超声（M-HIFU）以微空化为主的新型治疗小鼠癌症模型中验证了这一概念。在这里，我们阐明了 M-HIFU 相对于传统热高强度聚焦超声 (T-HIFU) 增强抗肿瘤免疫力的机制，并研究了与免疫检查点抑制剂、抗 PD-L1 抗体组合策略的潜力。分别在 C57BL/6 或 BALB/c 小鼠中使用三阴性 (E0771) 或人 ErbB-2 (HER2) 表达 (MM3MG-HER2) 肿瘤，在同基因小鼠乳腺癌模型中研究治疗的抗肿瘤功效。使用双侧肿瘤植入模型测试了治疗对全身抗肿瘤免疫的诱导。通过流式细胞术、免疫组织化学和单细胞 RNA 测序来阐明 HIFU 治疗或联合治疗对 TME 的详细影响，包括 CD8 T 细胞的激活状态和肿瘤相关巨噬细胞 (TAM) 的极化。与 T-HIFU 相比，M-HIFU 诱导更有效的全身抗肿瘤免疫和肿瘤生长抑制。通过单细胞 RNA 测序对 M-HIFU 后的 TME 进行分子表征，表明与 T-HIFU 后的 TME 相比，TAM 复极化为免疫刺激性 M1 亚型。与 M-HIFU 单一疗法相比，在 M-HIFU 治疗的小鼠中，同时施用抗 PD-L1 抗体或消除含有调节性 T 细胞群的 CD4+ T 细胞，显着增加了 T 细胞介导的抗肿瘤免疫和远处未治疗肿瘤部位的肿瘤生长抑制。 CD8 T 细胞和自然杀伤细胞在联合治疗中作为效应细胞发挥了主要作用。 M-HIFU 对 TME 的物理破坏使 TAM 重新极化，增强 T 细胞浸润，并且当与抗 PD-L1 抗体结合时，可介导卓越的全身抗肿瘤免疫反应和远处肿瘤生长抑制。这些发现表明，当应用于原发性肿瘤时，M-HIFU 联合抗 PD-L1 可能有助于减少晚期复发或转移。
Despite multimodal adjuvant management with radiotherapy, chemotherapy and hormonal therapies, most surgically resected primary breast cancers relapse or metastasize. A potential solution to late and distant recurrence is to augment systemic antitumor immunity, in part by appropriately presenting tumor antigens, but also by modulating the immunosuppressive tumor microenvironment (TME). We previously validated this concept in models of murine carcinoma treated with a novel predominately microcavitating version of high-intensity focused ultrasound (HIFU), mechanical high-intensity focused ultrasound (M-HIFU). Here we elucidated the mechanisms of enhanced antitumor immunity by M-HIFU over conventional thermal high-intensity focused ultrasound (T-HIFU) and investigated the potential of the combinatorial strategy with an immune checkpoint inhibitor, anti-PD-L1 antibody. The antitumor efficacy of treatments was investigated in syngeneic murine breast cancer models using triple-negative (E0771) or human ErbB-2 (HER2) expressing (MM3MG-HER2) tumors in C57BL/6 or BALB/c mice, respectively. Induction of systemic antitumor immunity by the treatments was tested using bilateral tumor implantation models. Flow cytometry, immunohistochemistry, and single-cell RNA sequencing were performed to elucidate detailed effects of HIFU treatments or combination treatment on TME, including the activation status of CD8 T cells and polarization of tumor-associated macrophages (TAMs). More potent systemic antitumor immunity and tumor growth suppression were induced by M-HIFU compared with T-HIFU. Molecular characterization of the TME after M-HIFU by single-cell RNA sequencing demonstrated repolarization of TAM to the immunostimulatory M1 subtype compared with TME post-T-HIFU. Concurrent anti-PD-L1 antibody administration or depletion of CD4+ T cells containing a population of regulatory T cells markedly increased T cell-mediated antitumor immunity and tumor growth suppression at distant, untreated tumor sites in M-HIFU treated mice compared with M-HIFU monotherapy. CD8 T and natural killer cells played major roles as effector cells in the combination treatment. Physical disruption of the TME by M-HIFU repolarizes TAM, enhances T-cell infiltration, and, when combined with anti-PD-L1 antibody, mediates superior systemic antitumor immune responses and distant tumor growth suppression. These findings suggest M-HIFU combined with anti-PD-L1 may be useful in reducing late recurrence or metastasis when applied to primary tumors.
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影响因子：
3.7
作者：
Jablonski KA;Amici SA;Webb LM;Ruiz-Rosado Jde D;Popovich PG;Partida-Sanchez S;Guerau-de-Arellano M
通讯作者：
Guerau-de-Arellano M
影响因子：
4.6
作者：
Fite BZ;Wang J;Kare AJ;Ilovitsh A;Chavez M;Ilovitsh T;Zhang N;Chen W;Robinson E;Zhang H;Kheirolomoom A;Silvestrini MT;Ingham ES;Mahakian LM;Tam SM;Davis RR;Tepper CG;Borowsky AD;Ferrara KW
通讯作者：
Ferrara KW
影响因子：
15.9
作者：
Fadok, VA;Bratton, DL;Henson, PM
通讯作者：
Henson, PM
影响因子：
78.5
作者：
Kennedy, JE
通讯作者：
Kennedy, JE
影响因子：
50.3
作者：
Cassetta, Luca;Fragkogianni, Stamatina;Pollard, Jeffrey W.
通讯作者：
Pollard, Jeffrey W.