Low molecular weight heparin synergistically enhances the efficacy of adoptive and anti-PD-1-based immunotherapy by increasing lymphocyte infiltration in colorectal cancer.
Low molecular weight heparin synergistically enhances the efficacy of adoptive and anti-PD-1-based immunotherapy by increasing lymphocyte infiltration in colorectal cancer.
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DOI：
10.1136/jitc-2023-007080
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发表时间：
2023-08
影响因子：
10.9
通讯作者：
Wei, Fang
中科院分区：
文献类型：
--
作者：
Quan, Yibo;He, Jie;Zou, Qi;Zhang, Liuxi;Sun, Qihui;Huang, Hongli;Li, Wanglin;Xie, Keping;Wei, Fang
关键词：
免疫疗法，包括过继细胞疗法（ACT）和免疫检查点抑制剂（ICIs），对大多数结直肠癌（CRC）患者的疗效有限，对肝转移患者的疗效进一步有限。缺乏抗肿瘤淋巴细胞浸润可能是主要原因，目前仍迫切需要更有效、更安全的CRC治疗方法。本研究充分评价了低分子肝素（LMWH）联合免疫治疗在微卫星稳定（MSS）高侵袭性小鼠CRC模型中的抗肿瘤增效作用。低分子肝素和ACT双重作用客观上介导了肿瘤生长停滞和肝转移抑制，低分子肝素和ACT单独作用均无抗肿瘤活性。多重免疫组化、纯化CD8+ T细胞转移试验及IVIM体内显像显示，低分子肝素联合ACT明显增加了肿瘤内CD8+ T细胞的浸润。机制上，对肿瘤微环境变化的评估显示，低分子肝素改善了肿瘤血管正常化，促进了活化的CD8+ T细胞进入肿瘤。同样，在小鼠CT26肿瘤模型中，低分子肝素联合抗程序性细胞死亡蛋白1 （PD-1）治疗比单独阻断PD-1治疗具有更好的抗肿瘤活性。低分子肝素可以通过增加淋巴细胞对肿瘤的浸润，特别是细胞毒性CD8+ T细胞的浸润来增强ACT和icis免疫治疗。这些结果表明，低分子肝素结合免疫治疗策略是一种有希望和安全的CRC治疗方法，特别是在MSS肿瘤中。
Immunotherapy, including adoptive cell therapy (ACT) and immune checkpoint inhibitors (ICIs), has a limited effect in most patients with colorectal cancer (CRC), and the efficacy is further limited in patients with liver metastasis. Lack of antitumor lymphocyte infiltration could be a major cause, and there remains an urgent need for more potent and safer therapies for CRC. In this study, the antitumoral synergism of low molecular weight heparin (LMWH) combined with immunotherapy in the microsatellite stable (MSS) highly aggressive murine model of CRC was fully evaluated. Dual LMWH and ACT objectively mediated the stagnation of tumor growth and inhibition of liver metastasis, neither LMWH nor ACT alone had any antitumoral activity on them. The combination of LMWH and ACT obviously increased the infiltration of intratumor CD8+ T cells, as revealed by multiplex immunohistochemistry, purified CD8+ T-cell transfer assay, and IVIM in vivo imaging. Mechanistically, evaluation of changes in the tumor microenvironment revealed that LMWH improved tumor vascular normalization and facilitated the trafficking of activated CD8+ T cells into tumors. Similarly, LMWH combined with anti-programmed cell death protein 1 (PD-1) therapy provided superior antitumor activity as compared with the single PD-1 blockade in murine CT26 tumor models. LMWH could enhance ACT and ICIs-based immunotherapy by increasing lymphocyte infiltration into tumors, especially cytotoxic CD8+ T cells. These results indicate that combining LMWH with an immunotherapy strategy presents a promising and safe approach for CRC treatment, especially in MSS tumors.
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影响因子：
8.8
作者：
Ono, K;Ishihara, M;Ishikawa, K;Ozeki, Y;Deguchi, H;Sato, M;Hashimoto, H;Saito, Y;Yura, H;Kurita, A;Maehara, T
通讯作者：
Maehara, T
影响因子：
4.4
作者：
Bouzin, Caroline;Brouet, Agnes;Feron, Olivier
通讯作者：
Feron, Olivier
影响因子：
4
作者：
Ades, Steven;Pulluri, Bhargavi;Holmes, Chris E.;Lal, Inder;Kumar, Santosh;Littenberg, Benjamin
通讯作者：
Littenberg, Benjamin
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
发表时间：
2021-09-13
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Doleschel D;Hoff S;Koletnik S;Rix A;Zopf D;Kiessling F;Lederle W
通讯作者：
Lederle W
影响因子：
5.4
作者：
Goel, Shom;Wong, Andus Hon-Kit;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.