A novel combination of chemotherapy and immunotherapy controls tumor growth in mice with a human immune system
A novel combination of chemotherapy and immunotherapy controls tumor growth in mice with a human immune system
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DOI：
10.1080/2162402x.2019.1596005
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发表时间：
2019-04-07
期刊：
影响因子：
7.2
通讯作者：
Marodon, Gilles
中科院分区：
文献类型：
--
作者：
Burlion, Aude;Ramos, Rodrigo N.;Marodon, Gilles
用人类免疫系统重建并携带人类肿瘤的小鼠代表了开发新型癌症免疫疗法的有希望的模型。在这里，我们使用了大量的流式细胞术和多参数流式细胞术来表征人类白细胞浸润的人乳腺癌肿瘤模型中的免疫功能低下的NOD.SCID. γ c-空小鼠重建与人类免疫系统，并将其与乳腺癌患者的样本进行比较。我们在肿瘤中观察到高度活化的人CD 4（+）和CD 8（+）T细胞，以及两种情况下先天免疫细胞的次要亚群。我们还报道了ICOS+ CD 4（+）调节性T细胞（Treg）在人源化小鼠和患者的肿瘤中相对于外周富集，提供了影响Treg和肿瘤生长的靶点。事实上，在人源化小鼠中，对人ICOS施用中和mAb降低了Treg比例和数量并改善了CD 4 + T细胞增殖。此外，抗ICOS mAb与环磷酰胺的组合减少了肿瘤生长，并且这与改善的CD 8与Treg比率相关。人CD 8（+）T细胞或鼠骨髓细胞的耗竭轻微影响联合治疗的效果。总之，我们的结果表明，抗ICOS mAb和化疗的组合控制了人源化小鼠中的肿瘤生长，为乳腺癌的治疗开辟了新的前景。一句话总结：靶向ICOS联合化疗是提高人类肿瘤免疫力的一种有前途的策略。
Mice reconstituted with a human immune system and bearing human tumors represent a promising model for developing novel cancer immunotherapies. Here, we used mass cytometry and multi-parametric flow cytometry to characterize human leukocytes infiltrating a human breast cancer tumor model in immunocompromised NOD.SCID.gamma c-null mice reconstituted with a human immune system and compared it to samples of breast cancer patients. We observed highly activated human CD4(+) and CD8(+) T cells in the tumor, as well as minor subsets of innate immune cells in both settings. We also report that ICOS+ CD4(+) regulatory T cells (Treg) were enriched in the tumor relative to the periphery in humanized mice and patients, providing a target to affect Treg and tumor growth. Indeed, administration of a neutralizing mAb to human ICOS reduced Treg proportions and numbers and improved CD4 + T cell proliferation in humanized mice. Moreover, a combination of the anti-ICOS mAb with cyclophosphamide reduced tumor growth, and that was associated with an improved CD8 to Treg ratio. Depletion of human CD8(+) T cells or of murine myeloid cells marginally affected the effect of the combination therapy. Altogether, our results indicate that a combination of anti-ICOS mAb and chemotherapy controls tumor growth in humanized mice, opening new perspectives for the treatment of breast cancer. One sentence summary: Targeting ICOS in combination with chemotherapy is a promising strategy to improve tumor immunity in humans.