PDF(Pubmed)
Abstract：
Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.
摘要：
最近的临床研究表明，癌细胞中10号染色体（PTEN）基因缺失的磷酸酶和张力蛋白同源物的突变可能与免疫抑制肿瘤微环境（TME）和对免疫检查点阻断（ICB）治疗的反应不良有关。因此,有效恢复癌细胞中PTEN基因的表达对于提高ICB治疗的应答率至关重要。这里,我们筛选了腺相关病毒（AAV）衣壳，用于将PTEN基因有效递送到B16F10肿瘤细胞中。我们证明瘤内注射AAV6-PTEN通过诱导肿瘤细胞免疫原性细胞死亡（ICD）和增加免疫细胞浸润，成功恢复了肿瘤细胞PTEN基因表达并有效抑制了肿瘤进展。此外，我们开发了一种抗PD-1负载磷脂的相分离凝胶（PPSG），形成原位储库，并在体内42天内可持续释放抗PD-1药物。为了有效抑制黑色素瘤的复发，我们进一步应用了基于AAV6-PTEN的三联疗法，PPSG@anti-PD-1和CpG,并表明这种三联疗法策略增强了协同抗肿瘤免疫作用，也诱导了强大的免疫记忆，完全拒绝肿瘤复发。我们预计这种三联疗法可以作为一种新的肿瘤联合疗法，具有更强的免疫激活能力和肿瘤抑制功效。
