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基于生物材料的支架用于原位化学免疫治疗以治疗免疫原性差的肿瘤。

Biomaterial-based scaffold for in situ chemo-immunotherapy to treat poorly immunogenic tumors.

机构信息

Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, 02138, USA.

Wyss Institute for Biologically Inspired Engineering, Cambridge, Massachusetts, 02138, USA.

出版信息

Nat Commun. 2020 Nov 10;11(1):5696. doi: 10.1038/s41467-020-19540-z.

DOI:10.1038/s41467-020-19540-z
PMID:33173046
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7655953/
Abstract

Poorly immunogenic tumors, including triple negative breast cancers (TNBCs), remain resistant to current immunotherapies, due in part to the difficulty of reprogramming the highly immunosuppressive tumor microenvironment (TME). Here we show that peritumorally injected, macroporous alginate gels loaded with granulocyte-macrophage colony-stimulating factor (GM-CSF) for concentrating dendritic cells (DCs), CpG oligonucleotides, and a doxorubicin-iRGD conjugate enhance the immunogenic death of tumor cells, increase systemic tumor-specific CD8 + T cells, repolarize tumor-associated macrophages towards an inflammatory M1-like phenotype, and significantly improve antitumor efficacy against poorly immunogenic TNBCs. This system also prevents tumor recurrence after surgical resection and results in 100% metastasis-free survival upon re-challenge. This chemo-immunotherapy that concentrates DCs to present endogenous tumor antigens generated in situ may broadly serve as a facile platform to modulate the suppressive TME, and enable in situ personalized cancer vaccination.

摘要

免疫原性差的肿瘤，包括三阴性乳腺癌（TNBC），仍然对目前的免疫疗法有抗性，部分原因是难以重新编程高度免疫抑制的肿瘤微环境（TME）。在这里，我们表明，在肿瘤周围注射载有粒细胞-巨噬细胞集落刺激因子（GM-CSF）的大孔海藻酸盐凝胶，用于浓缩树突状细胞（DC）、CpG 寡核苷酸和阿霉素-iRGD 缀合物，可增强肿瘤细胞的免疫原性死亡，增加全身肿瘤特异性 CD8+T 细胞，使肿瘤相关巨噬细胞向炎症性 M1 样表型极化，并显著提高针对免疫原性差的 TNBC 的抗肿瘤疗效。该系统还可以防止手术后肿瘤复发，并在重新挑战时实现 100%无转移生存。这种将 DC 浓缩以呈现原位产生的内源性肿瘤抗原的化学免疫疗法可能广泛用作调节抑制性 TME 的简便平台，并实现原位个性化癌症疫苗接种。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3188/7655953/46ad1e436e4d/41467_2020_19540_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3188/7655953/062ff89fdc34/41467_2020_19540_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3188/7655953/bd1226eaa661/41467_2020_19540_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3188/7655953/46ad1e436e4d/41467_2020_19540_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3188/7655953/5b984d29b201/41467_2020_19540_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3188/7655953/a9e68ee914b6/41467_2020_19540_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3188/7655953/3d825096ca3f/41467_2020_19540_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3188/7655953/a2287fc8c4db/41467_2020_19540_Fig4_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3188/7655953/bd1226eaa661/41467_2020_19540_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3188/7655953/46ad1e436e4d/41467_2020_19540_Fig7_HTML.jpg

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