PDF(Pubmed)
Abstract：
Despite the great potential of anti-PD-L1 antibodies for immunotherapy, their low response rate due to an immunosuppressive tumor microenvironment has hampered their application. To address this issue, we constructed a cell membrane-coated nanosystem (mB4S) to reverse an immunosuppressive microenvironment to an immuno-supportive one for strengthening the anti-tumor effect. In this system, Epirubicin (EPI) as an immunogenic cell death (ICD) inducer was coupled to a branched glycopolymer via hydrazone bonds and diABZI as a stimulator of interferon genes (STING) agonist was encapsulated into mB4S. After internalization of mB4S, EPI was acidic-responsively released to induce ICD, which was characterized by an increased level of calreticulin (CRT) exposure and enhanced ATP secretion. Meanwhile, diABZI effectively activated the STING pathway. Treatment with mB4S in combination with an anti-PD-L1 antibody elicited potent immune responses by increasing the ratio of matured dendritic cells (DCs) and CD8+ T cells, promoting cytokines secretion, up-regulating M1-like tumor-associated macrophages (TAMs) and down-regulating immunosuppressive myeloid-derived suppressor cells (MDSCs). Therefore, this nanosystem for co-delivery of an ICD inducer and a STING agonist achieved promotion of DCs maturation and CD8+ T cells infiltration, creating an immuno-supportive microenvironment, thus potentiating the therapy effect of the anti-PD-L1 antibody in both 4T1 breast and CT26 colon tumor mice.
摘要：
尽管抗PD-L1抗体用于免疫治疗的巨大潜力，由于免疫抑制的肿瘤微环境，它们的低反应率阻碍了它们的应用。为了解决这个问题，我们构建了一种细胞膜包被的纳米系统（mB4S），以将免疫抑制微环境逆转为免疫支持环境，以增强抗肿瘤作用。在这个系统中,作为免疫原性细胞死亡（ICD）诱导剂的表柔比星（EPI）通过腙键与支链的糖共聚物偶联，作为干扰素基因（STING）激动剂的刺激剂的diABZI封装到mB4S中。在mB4S内化后，EPI是酸性响应性释放以诱导ICD，其特征是钙网蛋白（CRT）暴露水平增加和ATP分泌增强。同时,DiABZI有效激活STING途径。mB4S与抗PD-L1抗体联合治疗通过增加成熟树突状细胞（DCs）和CD8+T细胞的比例引起有效的免疫应答。促进细胞因子分泌，上调M1样肿瘤相关巨噬细胞（TAMs）和下调免疫抑制髓源性抑制细胞（MDSC）。因此,这种用于ICD诱导物和STING激动剂共递送的纳米系统实现了促进DC成熟和CD8+T细胞浸润，创造一个免疫支持的微环境，从而增强抗PD-L1抗体在4T1乳腺和CT26结肠肿瘤小鼠中的治疗效果。
