Regorafenib enhances anti-PD1 immunotherapy efficacy in murine colorectal cancers and their combination prevents tumor regrowth.
Regorafenib enhances anti-PD1 immunotherapy efficacy in murine colorectal cancers and their combination prevents tumor regrowth.
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雷莫非尼增强了鼠结直肠癌的抗PD1免疫疗法功效，它们的组合可防止肿瘤再生。
DOI：
10.1186/s13046-021-02043-0
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发表时间：
2021-09-13
期刊：
影响因子：
--
通讯作者：
Lederle W
中科院分区：
文献类型：
--
作者：
Doleschel D;Hoff S;Koletnik S;Rix A;Zopf D;Kiessling F;Lederle W
晚期结直肠癌（CRC）患者预后不良。目前正在临床试验中评估免疫疗法和抗血管生成剂的组合。在这项研究中，将多激酶抑制剂瑞戈非尼（REG）与抗程序性细胞死亡蛋白1（aPD 1）抗体在同基因小鼠微卫星稳定（MSS）CT 26和高突变MC 38结肠癌模型中联合使用，以获得对潜在药物协同作用的机制见解。在用不同剂量的REG和aPD 1单独或组合治疗下研究原位CT 26和皮下MC 38结肠癌的生长和进展。停药后研究持续效应。通过动态对比增强MRI、组织学和分子分析评估肿瘤微环境的变化。在这两种模型中，REG和aPD 1联合治疗与单药相比显著改善了抗肿瘤活性。然而，在CT 26模型中，aPD 1的附加益处仅在治疗停止后变得明显。联合治疗有效地防止了肿瘤的再生长，并完全抑制了肝转移，而单独使用REG的抗肿瘤作用在停药后不久就消失了。在治疗期间，REG显著减少免疫抑制性巨噬细胞和调节性T（Treg）细胞向肿瘤微环境中的浸润。aPD 1显著增强瘤内IFNγ水平。这些药物协同诱导持续的M1极化和Treg细胞的持久减少，这可以解释持续的肿瘤抑制。这项研究强调了REG和aPD 1联合治疗在介导结肠癌再生长的持续抑制中的协同免疫调节作用，强烈支持CRC（包括MSS肿瘤）的临床评价。在线版本包含补充材料，可通过10.1186/s13046-021-02043-0获得。
Patients with advanced colorectal cancer (CRC) have a poor prognosis. Combinations of immunotherapies and anti-angiogenic agents are currently being evaluated in clinical trials. In this study, the multikinase inhibitor regorafenib (REG) was combined with an anti-programmed cell death protein 1 (aPD1) antibody in syngeneic murine microsatellite-stable (MSS) CT26 and hypermutated MC38 colon cancer models to gain mechanistic insights into potential drug synergism. Growth and progression of orthotopic CT26 and subcutaneous MC38 colon cancers were studied under treatment with varying doses of REG and aPD1 alone or in combination. Sustained effects were studied after treatment discontinuation. Changes in the tumor microenvironment were assessed by dynamic contrast-enhanced MRI, and histological and molecular analyses. In both models, REG and aPD1 combination therapy significantly improved anti-tumor activity compared with single agents. However, in the CT26 model, the additive benefit of aPD1 only became apparent after treatment cessation. The combination treatment efficiently prevented tumor regrowth and completely suppressed liver metastasis, whereas the anti-tumorigenic effects of REG alone were abrogated soon after drug discontinuation. During treatment, REG significantly reduced the infiltration of immunosuppressive macrophages and regulatory T (Treg) cells into the tumor microenvironment. aPD1 significantly enhanced intratumoral IFNγ levels. The drugs synergized to induce sustained M1 polarization and durable reduction of Treg cells, which can explain the sustained tumor suppression. This study highlights the synergistic immunomodulatory effects of REG and aPD1 combination therapy in mediating a sustained inhibition of colon cancer regrowth, strongly warranting clinical evaluation in CRC, including MSS tumors. The online version contains supplementary material available at 10.1186/s13046-021-02043-0.
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影响因子：
5.5
作者：
Du T;Han J
通讯作者：
Han J
影响因子：
4
作者：
Dhupkar P;Gordon N;Stewart J;Kleinerman ES
通讯作者：
Kleinerman ES
影响因子：
168.9
作者：
Bruix, Jordi;Qin, Shukui;Han, Guohong
通讯作者：
Han, Guohong
影响因子：
4.4
作者：
Castle JC;Loewer M;Boegel S;de Graaf J;Bender C;Tadmor AD;Boisguerin V;Bukur T;Sorn P;Paret C;Diken M;Kreiter S;Türeci Ö;Sahin U
通讯作者：
Sahin U
DOI：
10.1016/s0140-6736(12)61857-1
发表时间：
2013-01-26
期刊：
Lancet (London, England)
影响因子：
--
作者：
Demetri GD;Reichardt P;Kang YK;Blay JY;Rutkowski P;Gelderblom H;Hohenberger P;Leahy M;von Mehren M;Joensuu H;Badalamenti G;Blackstein M;Le Cesne A;Schöffski P;Maki RG;Bauer S;Nguyen BB;Xu J;Nishida T;Chung J;Kappeler C;Kuss I;Laurent D;Casali PG;GRID study investigators
通讯作者：
GRID study investigators