Polypeptide nanoformulation-induced immunogenic cell death and remission of immunosuppression for enhanced chemoimmunotherapy  

聚氨基酸纳米制剂诱导细胞免疫原性死亡并缓解免疫抑制以增强化疗免疫治疗

作　　者：Xiangru Feng Weiguo Xu Jianhua Liu Di Li Gao Li Jianxun Ding Xuesi Chen 冯祥汝;许维国;刘剑华;栗迪;李杲;丁建勋;陈学思(Key Laboratory of Polymer Ecomaterials,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun 130022,China;School of Applied Chemistry and Engineering,University of Science and Technology of China,Hefei 230026,China)

机构地区：[1]Key Laboratory of Polymer Ecomaterials,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun 130022,China [2]School of Applied Chemistry and Engineering,University of Science and Technology of China,Hefei 230026,China

出　　处：《Science Bulletin》2021年第4期362-373,M0004,共13页科学通报（英文版）

基　　金：supported by the National Natural Science Foundation of China(51973216,51873207,51803006,51833010,51673190,and 51603204);the Science and Technology Development Program of Jilin Province(20200404182YY);the Youth Talents Promotion Project of Jilin Province(181909);the Youth Innovation Promotion Association of Chinese Academy of Sciences(2019005)。

摘　　要：Many conventional chemotherapeutics play an immune-modulating effect by inducing immunogenic cell death(ICD)in tumor cells.However,they hardly arouse strong antitumor immune response because the immunosuppressive lymphocytes are present in the tumor microenvironment.These immunosuppressive lymphocytes include regulatory T cells(Tregs)and myeloid-derived suppressor cells(MDSCs).We used a low dose of doxorubicin(DOX)to induce ICD in combination with immune regulator 1-methylDL-tryptophan(1 MT)to suppress indoleamine 2,3-dioxygenase and overcome Treg-and MDSCassociated immune suppression.By co-encapsulation of DOX and 1 MT into a reduction-responsive polypeptide nanogel,the drugs were simultaneously released in the tumor cells and synergistically performed antitumor efficacy.After treatment,recruitment of Tregs and MDSCs was inhibited,and the frequency of tumor-infiltrating CD8+T cells was remarkably enhanced.These results demonstrated that the chemoimmunotherapy strategy effectively suppressed tumor growth without causing evident adverse effects,indicating its great potential in clinical cancer therapy.许多传统化疗药物通过诱导肿瘤细胞发生免疫原性细胞死亡(ICD)而发挥免疫调节功能.但是,由于肿瘤微环境中存在免疫抑制性淋巴细胞,如调节性T细胞(Treg)和骨髓来源的抑制性细胞(MDSC),ICD很难引起有效的抗肿瘤免疫反应.本文利用低剂量的阿霉素(DOX)作为ICD诱导剂,与免疫调节药物1-甲基-DL-色氨酸(1MT)联合用于肿瘤化疗免疫治疗.1MT能够通过抑制吲哚胺2,3-双加氧酶的活性干扰Treg和MDSC的功能,从而克服肿瘤的免疫抑制状态.将DOX与1MT共同负载于还原响应性的聚氨基酸纳米凝胶中,两种药物同时在肿瘤细胞中释放,发挥协同抗肿瘤功能.治疗后,肿瘤局部Treg和MDSC的募集受到抑制,CD8+T细胞的比例显著升高.结果表明,这一化疗免疫治疗策略可有效抑制肿瘤生长,且不产生明显副作用,在临床癌症治疗中具有应用潜力.

关 键 词：Polypeptide nanogel Controlled drug release Immunogenic cell death Remission of Immunosuppression CHEMOIMMUNOTHERAPY 

分 类 号：R730.51[医药卫生—肿瘤]