Stromal and tumor immune microenvironment reprogramming through multifunctional cisplatin-based liposomes boosts the efficacy of anti-PD-1 immunotherapy in pancreatic cancer
Stromal and tumor immune microenvironment reprogramming through multifunctional cisplatin-based liposomes boosts the efficacy of anti-PD-1 immunotherapy in pancreatic cancer
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DOI：
10.1039/d3bm01118f
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发表时间：
2023-11-03
影响因子：
6.6
通讯作者：
Yan，Pengke
中科院分区：
文献类型：
--
作者：
Yu，Hang;Zhu，Wenting;Yan，Pengke
胰腺癌组织中致密的间质屏障阻断了化疗药物和治疗性抗体的肿瘤内递送和分布，导致化学免疫治疗反应较差。我们设计了一种多靶向pH敏感性脂质体，其将顺铂（Pt）封装在其水核中（表示为ATF@Pt LPS），并对胰腺癌细胞、肿瘤相关巨噬细胞和癌症相关成纤维细胞中的uPAR受体显示出高亲和力。全身施用ATF@Pt LPS能够克服中央基质细胞屏障并有效地将药物递送到肿瘤细胞中，从而在Panc 02细胞衍生的移植肿瘤小鼠模型中产生强烈的治疗反应。更重要的是，胶原蛋白的ATF@Pt Lps降解有助于CD 8 + T细胞向肿瘤中的浸润以及抗PD-1单克隆抗体的增强积累。此外，Pt杀死肿瘤细胞还导致肿瘤抗原的释放，其促进免疫细胞，特别是CD 83+细胞、Th 1 CD 4+细胞和CD 8+细胞毒性T细胞的增殖，将免疫评分“冷”胰腺癌转化为促免疫“热”肿瘤。与免疫检查点剂（抑制PD-1的抗PD-1抗体）的进一步组合可以增强肿瘤特异性细胞毒性T细胞反应。因此，ATF@Pt Lps显示出多靶向、受控药物释放、基质破坏、增强的渗透、杀死癌细胞、修饰免疫抑制微环境和增强免疫力。该研究为进一步开发ATF@Pt Lps和抗PD-1抗体的组合用于胰腺癌的有效治疗提供了重要的机制信息。
The dense stromal barrier in pancreatic cancer tissues blocks intratumoral delivery and distribution of chemotherapeutics and therapeutic antibodies, causing poor chemoimmunotherapy responses. We designed a multi-targeted pH-sensitive liposome which encapsulates cisplatin (Pt) in its water core (denoted as ATF@Pt Lps) and shows high affinity for uPAR receptors in pancreatic cancer cells, tumor-associated macrophages, and cancer-associated fibroblasts. Systemic administration of ATF@Pt Lps enabled overcoming the central stromal cellular barrier and effective drug delivery into tumor cells, resulting in a strong therapeutic response in a Panc02 cell derived transplanted tumor mouse model. More importantly, ATF@Pt Lps degradation of collagen contributes to the infiltration of CD8+ T cells into tumors as well as an enhanced accumulation of anti PD-1 monoclonal antibodies. Furthermore, the killing of tumor cells by Pt also leads to the release of tumor antigens, which promote the proliferation of immune cells, especially CD83+ cells, Th1 CD4+ cells, and CD8+ cytotoxic T cells, that converted an immunoscore “cold” pancreatic cancer into a pro-immune “hot” tumor. A further combination with an immune checkpoint agent, anti PD-1 antibodies that inhibit PD-1, can enhance tumor specific cytotoxic T cell response. Accordingly, ATF@Pt Lps displays multi-targeting, controlled drug release, stromal disruption, enhanced penetration, killing of cancer cells, modification of the immunosuppressive microenvironment, and enhancement of immunity. This study provides important mechanistic information for the further development of a combination of ATF@Pt Lps and anti PD-1 antibodies for the effective treatment of pancreatic cancer.