Pallasch, Christian P. ORCID: 0000-0001-5675-6905, Leskov, Ilya, Braun, Christian J., Vorholt, Daniela, Drake, Adam, Soto-Feliciano, Yadira M., Bent, Eric H., Schwamb, Janine, Iliopoulou, Bettina, Kutsch, Nadine, van Rooijen, Nico, Frenzel, Lukas P., Wendtner, Clemens M., Heukamp, Lukas ORCID: 0000-0002-3388-3482, Kreuzer, Karl Anton, Hallek, Michael, Chen, Jianzhu and Hemann, Michael T. (2014). Sensitizing Protective Tumor Microenvironments to Antibody-Mediated Therapy. Cell, 156 (3). S. 590 - 603. CAMBRIDGE: CELL PRESS. ISSN 1097-4172

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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 TNFa 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Pallasch, Christian P.UNSPECIFIEDorcid.org/0000-0001-5675-6905UNSPECIFIED
Leskov, IlyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braun, Christian J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vorholt, DanielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Drake, AdamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soto-Feliciano, Yadira M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bent, Eric H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwamb, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iliopoulou, BettinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kutsch, NadineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Rooijen, NicoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frenzel, Lukas P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wendtner, Clemens M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heukamp, LukasUNSPECIFIEDorcid.org/0000-0002-3388-3482UNSPECIFIED
Kreuzer, Karl AntonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, JianzhuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hemann, Michael T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-448046
DOI: 10.1016/j.cell.2013.12.041
Journal or Publication Title: Cell
Volume: 156
Number: 3
Page Range: S. 590 - 603
Date: 2014
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1097-4172
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CHRONIC LYMPHOCYTIC-LEUKEMIA; INITIAL THERAPY; RITUXIMAB; LYMPHOMA; CYCLOPHOSPHAMIDE; FLUDARABINE; CANCER; CELLS; CHEMOTHERAPY; MACROPHAGESMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/44804

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