PDF(Pubmed)
Abstract：
Dendritic cell (DC)-based vaccines have emerged as a promising strategy in cancer immunotherapy due to low toxicity. However, the therapeutic efficacy of DC as a monotherapy is insufficient due to highly immunosuppressive tumor environment. To address these limitations of DC as immunotherapeutic agent, we have developed a polymeric nanocomplex incorporating (1) oncolytic adenovirus (oAd) co-expressing interleukin (IL)-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF) and (2) arginine-grafted bioreducible polymer with PEGylated paclitaxel (APP) to restore antitumor immune surveillance function in tumor milieu and potentiate immunostimulatory attributes of DC vaccine. Nanohybrid complex (oAd/APP) in combination with DC (oAd/APP+DC) induced superior expression level of antitumor cytokines (IL-12, GM-CSF, and interferon gamma) than either oAd/APP or DC monotherapy in tumor tissues, thus resulting in superior intratumoral infiltration of both endogenous and exogenous DCs. Furthermore, oAd/APP+DC treatment led superior migration of DC to secondary lymphoid organs, such as draining lymph nodes and spleen, in comparison with either monotherapy. Superior migration profile of DCs in oAd/APP+DC treatment group resulted in more prolific activation of tumor-specific T cells in these lymphoid organs and greater intratumoral infiltration of T cells. Additionally, oAd/APP+DC treatment led to lower subset of tumor infiltrating lymphocytes and splenocytes being immunosuppressive regulatory T cells than any other treatment groups. Collectively, oAd/APP+DC led to superior induction of antitumor immune response and amelioration of immunosuppressive tumor microenvironment to elicit potent tumor growth inhibition than either monotherapy.
摘要：
由于低毒性，基于树突状细胞（DC）的疫苗已成为癌症免疫疗法中一种有前途的策略。然而,由于高度免疫抑制的肿瘤环境,DC作为单一疗法的疗效不足.为了解决DC作为免疫治疗剂的这些局限性，我们开发了一种聚合物纳米复合物,该复合物包含(1)共表达白细胞介素(IL)-12和粒细胞-巨噬细胞集落刺激因子(GM-CSF)的溶瘤腺病毒(oAd)和(2)与聚乙二醇化紫杉醇(APP)的精氨酸接枝生物可还原聚合物,以恢复肿瘤环境中的抗肿瘤免疫监视功能并增强DC疫苗的免疫刺激特性.纳米杂合复合物（oAd/APP）与DC（oAd/APP+DC）联合诱导抗肿瘤细胞因子（IL-12，GM-CSF，和干扰素γ）比肿瘤组织中的oAd/APP或DC单一疗法，因此导致内源性和外源性DC的肿瘤内浸润。此外，oAd/APP+DC治疗导致DC向次级淋巴器官的高级迁移，例如引流淋巴结和脾脏，与任一单一疗法相比。oAd/APP+DC治疗组中DC的优越迁移谱导致这些淋巴器官中肿瘤特异性T细胞的更多激活和T细胞的更大肿瘤内浸润。此外,oAd/APP+DC治疗导致比任何其他治疗组低的肿瘤浸润淋巴细胞和脾细胞亚群是免疫抑制性调节性T细胞。总的来说，与任何一种单一疗法相比，oAd/APPDC能更好地诱导抗肿瘤免疫反应，并改善免疫抑制性肿瘤微环境，从而引起有效的肿瘤生长抑制。
