肿瘤微环境
生物
癌症研究
骨髓
白血病
免疫系统
免疫学
渗透(HVAC)
肿瘤坏死因子α
巨噬细胞
抗体
先天免疫系统
体外
生物化学
热力学
物理
作者
Christian P. Pallasch,Ilya Leskov,Christian Braun,Daniela Vorholt,Adam Drake,Yadira M. Soto‐Feliciano,Eric H. Bent,Janine Schwamb,Bettina P. Iliopoulou,Nadine Kutsch,Nico van Rooijen,Lukas P. Frenzel,Clemens‐Martin Wendtner,Lukas C. Heukamp,Karl Kreuzer,Michael Hallek,Jianzhu Chen,Michael T. Hemann
出处
期刊:Cell
[Elsevier]
日期:2014-01-01
卷期号:156 (3): 590-602
被引量:157
标识
DOI:10.1016/j.cell.2013.12.041
摘要
Therapy-resistant microenvironments represent a major barrier toward effective elimination of disseminated malignancies. Here, we show that select microenvironments can underlie resistance to antibody-based therapy. Using a humanized model of treatment refractory B cell leukemia, we find that infiltration of leukemia cells into the bone marrow rewires the tumor microenvironment to inhibit engulfment of antibody-targeted tumor cells. Resistance to macrophage-mediated killing can be overcome by combination regimens involving therapeutic antibodies and chemotherapy. Specifically, the nitrogen mustard cyclophosphamide induces an acute secretory activating phenotype (ASAP), releasing CCL4, IL8, VEGF, and TNFα from treated tumor cells. These factors induce macrophage infiltration and phagocytic activity in the bone marrow. Thus, the acute induction of stress-related cytokines can effectively target cancer cells for removal by the innate immune system. This synergistic chemoimmunotherapeutic regimen represents a potent strategy for using conventional anticancer agents to alter the tumor microenvironment and promote the efficacy of targeted therapeutics.
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