Sensitizing Protective Tumor Microenvironments to Antibody-Mediated Therapy
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 infilt...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2015
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| Online Access: | http://hdl.handle.net/1721.1/96265 https://orcid.org/0000-0001-5118-8478 https://orcid.org/0000-0002-5229-8748 https://orcid.org/0000-0002-5687-6154 https://orcid.org/0000-0002-6604-2129 |
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| author | Pallasch, Christian Leskov, Ilya B. Vorholt, Daniela Drake, Adam Bent, Eric H. Schwamb, Janine Iliopoulou, Bettina P. Kutsch, Nadine van Rooijen, Nico Frenzel, Lukas P. Wendtner, Clemens M. Heukamp, Lukas Kreuzer, Karl Anton Hallek, Michael Chen, Jianzhu Braun, Christian Joerg Soto Feliciano, Yadira Marie Hemann, Michael |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Pallasch, Christian Leskov, Ilya B. Vorholt, Daniela Drake, Adam Bent, Eric H. Schwamb, Janine Iliopoulou, Bettina P. Kutsch, Nadine van Rooijen, Nico Frenzel, Lukas P. Wendtner, Clemens M. Heukamp, Lukas Kreuzer, Karl Anton Hallek, Michael Chen, Jianzhu Braun, Christian Joerg Soto Feliciano, Yadira Marie Hemann, Michael |
| author_sort | Pallasch, Christian |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T15:02:19Z |
| format | Article |
| id | mit-1721.1/96265 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:02:19Z |
| publishDate | 2015 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/962652022-09-29T12:11:47Z Sensitizing Protective Tumor Microenvironments to Antibody-Mediated Therapy Pallasch, Christian Leskov, Ilya B. Vorholt, Daniela Drake, Adam Bent, Eric H. Schwamb, Janine Iliopoulou, Bettina P. Kutsch, Nadine van Rooijen, Nico Frenzel, Lukas P. Wendtner, Clemens M. Heukamp, Lukas Kreuzer, Karl Anton Hallek, Michael Chen, Jianzhu Braun, Christian Joerg Soto Feliciano, Yadira Marie Hemann, Michael Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Pallasch, Christian Leskov, Ilya B. Braun, Christian Joerg Drake, Adam Soto Feliciano, Yadira Marie Bent, Eric H. Iliopoulou, Bettina P. Chen, Jianzhu Hemann, Michael 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. Massachusetts Institute of Technology. Ludwig Center for Molecular Oncology Kathy and Curt Marble Cancer Research Fund Singapore-MIT Alliance for Research and Technology German Research Foundation (KFO286) German Research Foundation (Fellowship) National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051) 2015-03-30T19:46:14Z 2015-03-30T19:46:14Z 2014-01 2013-08 Article http://purl.org/eprint/type/JournalArticle 00928674 1097-4172 http://hdl.handle.net/1721.1/96265 Pallasch, Christian P., Ilya Leskov, Christian J. Braun, Daniela Vorholt, Adam Drake, Yadira M. Soto-Feliciano, Eric H. Bent, et al. “Sensitizing Protective Tumor Microenvironments to Antibody-Mediated Therapy.” Cell 156, no. 3 (January 2014): 590–602. © 2014 Elsevier Inc. https://orcid.org/0000-0001-5118-8478 https://orcid.org/0000-0002-5229-8748 https://orcid.org/0000-0002-5687-6154 https://orcid.org/0000-0002-6604-2129 en_US http://dx.doi.org/10.1016/j.cell.2013.12.041 Cell Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Elsevier Elsevier Open Archive |
| spellingShingle | Pallasch, Christian Leskov, Ilya B. Vorholt, Daniela Drake, Adam Bent, Eric H. Schwamb, Janine Iliopoulou, Bettina P. Kutsch, Nadine van Rooijen, Nico Frenzel, Lukas P. Wendtner, Clemens M. Heukamp, Lukas Kreuzer, Karl Anton Hallek, Michael Chen, Jianzhu Braun, Christian Joerg Soto Feliciano, Yadira Marie Hemann, Michael Sensitizing Protective Tumor Microenvironments to Antibody-Mediated Therapy |
| title | Sensitizing Protective Tumor Microenvironments to Antibody-Mediated Therapy |
| title_full | Sensitizing Protective Tumor Microenvironments to Antibody-Mediated Therapy |
| title_fullStr | Sensitizing Protective Tumor Microenvironments to Antibody-Mediated Therapy |
| title_full_unstemmed | Sensitizing Protective Tumor Microenvironments to Antibody-Mediated Therapy |
| title_short | Sensitizing Protective Tumor Microenvironments to Antibody-Mediated Therapy |
| title_sort | sensitizing protective tumor microenvironments to antibody mediated therapy |
| url | http://hdl.handle.net/1721.1/96265 https://orcid.org/0000-0001-5118-8478 https://orcid.org/0000-0002-5229-8748 https://orcid.org/0000-0002-5687-6154 https://orcid.org/0000-0002-6604-2129 |
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