Immune modulation by molecularly targeted photothermal ablation in a mouse model of advanced hepatocellular carcinoma and cirrhosis.
Immune modulation by molecularly targeted photothermal ablation in a mouse model of advanced hepatocellular carcinoma and cirrhosis.
复制标题
DOI：
10.1038/s41598-022-15948-3
复制
发表时间：
2022-08-24
影响因子：
4.6
通讯作者：
Sheth, Rahul A.
中科院分区：
文献类型：
--
作者：
Munoz, Nina M.;Dupuis, Crystal;Williams, Malea;Dixon, Katherine;McWatters, Amanda;Zhang, Jie;Pavuluri, Swathi;Rao, Arvind;Duda, Dan G.;Kaseb, Ahmed;Sheth, Rahul A.
免疫疗法是一种很有前景的肝细胞癌（HCC）新治疗方法，但HCC免疫疗法存在许多障碍，包括免疫抑制微环境和肝脏的“免疫耐受”。热疗治疗方式是早期 HCC 的标准治疗方法，并且已知热疗具有免疫调节作用。我们开发了一种分子靶向光热消融 (MTPA) 技术，可提供热可调、肿瘤特异性的热量产生。本研究的目的是评估 MTPA 在毒素诱导肝硬化背景下的免疫治疗耐药同系 HCC 小鼠模型中的形态学和免疫学影响。我们发现该模型的解剖、细胞和分子特征概括了晚期人类 HCC 的特征。根据免疫组织化学、流式细胞术和单细胞 RNA 测序数据，相对于单独的对照或免疫检查点治疗，MTPA 作为单一疗法以及与免疫检查点疗法联合显着增加了瘤内 CD3+ 和活化的 CD8+ T 细胞，同时减少了调节性 T 细胞。此外，我们还发现了 MTPA 对全身肿瘤免疫影响的证据，在原位肿瘤治疗后可抑制远端肿瘤生长。这项研究的结果表明，肿瘤特异性热疗可能有助于克服晚期 HCC 免疫治疗的耐药机制。
Immunotherapy is a promising new treatment approach for hepatocellular carcinoma (HCC), but there are numerous barriers to immunotherapy in HCC, including an immunosuppressive microenvironment and the “immunotolerance” of the liver. Hyperthermia treatment modalities are standard of care for early stage HCC, and hyperthermia is known to have immunomodulatory effects. We have developed a molecularly targeted photothermal ablation (MTPA) technology that provides thermally tunable, tumor-specific heat generation. The purpose of this study was to evaluate the morphologic and immunologic effects of MTPA in an immunotherapy-resistant syngeneic mouse model of HCC in a background of toxin-induced cirrhosis. We found that the anatomic, cellular, and molecular features of this model recapitulate the characteristics of advanced human HCC. MTPA as a monotherapy and in combination with immune checkpoint therapy significantly increased intratumoral CD3+ and activated CD8+ T cells while decreasing regulatory T cells relative to control or immune checkpoint therapy alone based on immunohistochemistry, flow cytometry, and single cell RNA sequencing data. Furthermore, we identified evidence of MTPA’s influence on systemic tumor immunity, with suppression of remote tumor growth following treatment of orthotopic tumors. The results of this study suggest that tumor-specific hyperthermia may help overcome resistance mechanisms to immunotherapy in advanced HCC.
登录
查看更多内容
影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
5.7
作者：
Ito, A;Tanaka, K;Kobayashi, T
通讯作者：
Kobayashi, T
影响因子：
19.7
作者：
Ahmed, Muneeb;Kumar, Gaurav;Goldberg, S. Nahum
通讯作者：
Goldberg, S. Nahum
影响因子：
158.5
作者：
Finn, Richard S.;Qin, Shukui;Cheng, Ann-Lii
通讯作者：
Cheng, Ann-Lii
影响因子：
15.9
作者：
Fisher, Daniel T.;Chen, Qing;Evans, Sharon S.
通讯作者：
Evans, Sharon S.