【摘要】 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.更多还原

【Abstract】 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.更多还原