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Cell. 2014 Jan 30;156(3):590-602. doi: 10.1016/j.cell.2013.12.041.

Sensitizing protective tumor microenvironments to antibody-mediated therapy.

Author information

1
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Internal Medicine, Center of Integrated Oncology, University of Cologne, Cologne 50931, Germany.
2
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3
Department of Internal Medicine, Center of Integrated Oncology, University of Cologne, Cologne 50931, Germany.
4
VFM Amsterdam 1081, Netherlands.
5
Department of Pathology, University Hospital of Cologne 50937, Germany.
6
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: jchen@mit.edu.
7
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: hemann@mit.edu.

Abstract

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.

PMID:
24485462
PMCID:
PMC3975171
DOI:
10.1016/j.cell.2013.12.041
[Indexed for MEDLINE]
Free PMC Article

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