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将NKT细胞激活剂α-半乳糖神经酰胺直接整合到重组单核细胞增生李斯特菌中可提高乳腺癌疫苗的疗效。

Direct incorporation of the NKT-cell activator α-galactosylceramide into a recombinant Listeria monocytogenes improves breast cancer vaccine efficacy.

作者信息

Singh M, Quispe-Tintaya W, Chandra D, Jahangir A, Venkataswamy M M, Ng T W, Sharma-Kharkwal S, Carreño L J, Porcelli S A, Gravekamp C

机构信息

Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.

1] Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA [2] Millennium Institute on Immunology and Immunotherapy, Facultad de Medicina, Universidad de Chile, Avenue Independencia #1027, Santiago 8380453, Chile.

出版信息

Br J Cancer. 2014 Nov 11;111(10):1945-54. doi: 10.1038/bjc.2014.486. Epub 2014 Oct 14.

DOI:10.1038/bjc.2014.486
PMID:25314062
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4229631/
Abstract

BACKGROUND

Immune suppression in the tumour microenvironment remains a major limitation to successful immunotherapy of cancer. In the current study, we analysed whether the natural killer T cell-activating glycolipid α-galactosylceramide could overcome immune suppression and improve vaccination against metastatic breast cancer.

METHODS

Mice with metastatic breast cancer (4T1 model) were therapeutically treated with a Listeria monocytogenes-based vaccine expressing tumour-associated antigen Mage-b followed by α-galactosylceramide as separate agents, or as a complex of α-galactosylceramide stably incorporated into Listeria-Mage-b. Effects on metastases, tumour weight, toxicity and immune responses were determined.

RESULTS

Sequential treatments of mice with established 4T1 breast carcinomas using Listeria-Mage-b followed by α-galactosylceramide as a separate agent was highly effective at reducing metastases, but was accompanied by severe liver toxicity. In contrast, combined therapy using Listeria-Mage-b modified by incorporation of α-galactosylceramide resulted in nearly complete elimination of metastases without toxicity. This was associated with a significant increase in the percentage of natural killer T cells in the spleen, and an increase in natural killer cell activity and in T cell responses to Mage-b.

CONCLUSIONS

Our results suggest that direct incorporation of α-galactosylceramide into a live bacterial vaccine vector is a promising non-toxic new approach for the treatment of metastatic breast cancer.

摘要

背景

肿瘤微环境中的免疫抑制仍然是癌症免疫治疗成功的主要限制因素。在本研究中，我们分析了天然杀伤性T细胞激活糖脂α-半乳糖神经酰胺是否能够克服免疫抑制并改善针对转移性乳腺癌的疫苗接种效果。

方法

对患有转移性乳腺癌的小鼠（4T1模型）进行治疗，先用表达肿瘤相关抗原Mage-b的基于单核细胞增生李斯特菌的疫苗进行治疗，随后分别使用α-半乳糖神经酰胺，或将α-半乳糖神经酰胺稳定整合到李斯特菌-Mage-b中形成复合物进行治疗。测定其对转移、肿瘤重量、毒性和免疫反应的影响。

结果

对于已建立4T1乳腺癌的小鼠，先用李斯特菌-Mage-b治疗，随后单独使用α-半乳糖神经酰胺进行序贯治疗，在减少转移方面非常有效，但伴有严重的肝毒性。相比之下，使用整合了α-半乳糖神经酰胺的李斯特菌-Mage-b进行联合治疗，几乎完全消除了转移且无毒性。这与脾脏中天然杀伤性T细胞百分比的显著增加、自然杀伤细胞活性的增加以及T细胞对Mage-b反应的增加有关。

结论

我们的结果表明，将α-半乳糖神经酰胺直接整合到活细菌疫苗载体中是一种有前景的无毒新方法，可用于治疗转移性乳腺癌。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3d1/4229631/5778e87a1c13/bjc2014486f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3d1/4229631/b1bbd95f624b/bjc2014486f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3d1/4229631/8e50571b9545/bjc2014486f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3d1/4229631/782b4e8a0cfe/bjc2014486f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3d1/4229631/630c67b9437e/bjc2014486f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3d1/4229631/79e04f3e676d/bjc2014486f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3d1/4229631/5778e87a1c13/bjc2014486f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3d1/4229631/b1bbd95f624b/bjc2014486f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3d1/4229631/8e50571b9545/bjc2014486f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3d1/4229631/782b4e8a0cfe/bjc2014486f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3d1/4229631/630c67b9437e/bjc2014486f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3d1/4229631/79e04f3e676d/bjc2014486f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3d1/4229631/5778e87a1c13/bjc2014486f6.jpg

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