Division of Pharmacoengineering and Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
Nanoscale. 2020 Feb 7;12(5):3400-3410. doi: 10.1039/c9nr09610h. Epub 2020 Jan 28.
Highly fibrotic and collagen-rich properties in desmoplastic melanoma (DM) result in an immune-suppressive fibrotic tumor microenvironment (TME) that resists clinical therapies. The different clinical and pathological properties, as compared to conventional melanoma, lead to delayed diagnosis and it is difficult to deliver drugs effectively due to fibrosis. Herein, we designed a chemo-immuno strategy focused on combining vaccination immunotherapy with multi-targeting sunitinib (SUN) nano-therapy to remodel TME and generate a robust immune response and a stronger synergistic anti-cancer effect. This strategy was evaluated side-by-side with non-desmoplastic melanoma and achieved significant improvement in therapeutic efficacy. The combination treatment was also synergistically assessed with the desmoplastic melanoma model. This strategy can remodel the fibrotic immunosuppressive TME and result in a robust cytotoxic T-cell response by reducing the collagen content, normalizing blood vessels, inhibiting tumor-associated fibroblasts and reducing high levels of suppressor immune cells. The modification of fibrotic immunosuppressive TME may serve as a good approach to further enhance immunotherapy for desmoplastic tumors.
促纤维性和富含胶原的特性使得促结缔组织增生性黑色素瘤（DM）形成了一种免疫抑制性的纤维性肿瘤微环境（TME），从而抵抗临床治疗。与传统黑色素瘤相比，DM 在临床和病理方面存在差异，导致诊断延迟，并且由于纤维化，难以有效输送药物。在此，我们设计了一种化疗免疫策略，重点是将疫苗免疫疗法与多靶点舒尼替尼（SUN）纳米治疗相结合，重塑 TME 并产生强大的免疫反应和更强的协同抗癌作用。该策略与非促结缔组织增生性黑色素瘤进行了平行评估，并在治疗效果方面取得了显著改善。还对该策略与促结缔组织增生性黑色素瘤模型进行了协同评估。该策略可以重塑纤维性免疫抑制性 TME，并通过降低胶原含量、使血管正常化、抑制肿瘤相关成纤维细胞和减少高水平的抑制性免疫细胞，产生强大的细胞毒性 T 细胞反应。纤维性免疫抑制性 TME 的改变可能是进一步增强促结缔组织增生性肿瘤免疫治疗的一种良好方法。
