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 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.
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.
Christian P
CP
Pallasch
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Ilya
I
Leskov
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Christian J
CJ
Braun
Department of Internal Medicine, Center of Integrated Oncology, University of Cologne, Cologne 50931, Germany.
Daniela
D
Vorholt
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Adam
A
Drake
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Yadira M
YM
Soto-Feliciano
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Eric H
EH
Bent
Department of Internal Medicine, Center of Integrated Oncology, University of Cologne, Cologne 50931, Germany.
Janine
J
Schwamb
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Bettina
B
Iliopoulou
Department of Internal Medicine, Center of Integrated Oncology, University of Cologne, Cologne 50931, Germany.
Nadine
N
Kutsch
VFM Amsterdam 1081, Netherlands.
Nico
N
van Rooijen
Department of Internal Medicine, Center of Integrated Oncology, University of Cologne, Cologne 50931, Germany.
Lukas P
LP
Frenzel
Department of Internal Medicine, Center of Integrated Oncology, University of Cologne, Cologne 50931, Germany.
Clemens M
CM
Wendtner
Department of Pathology, University Hospital of Cologne 50937, Germany.
Lukas
L
Heukamp
Department of Internal Medicine, Center of Integrated Oncology, University of Cologne, Cologne 50931, Germany.
Karl Anton
KA
Kreuzer
Department of Internal Medicine, Center of Integrated Oncology, University of Cologne, Cologne 50931, Germany.
Michael
M
Hallek
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: jchen@mit.edu.
Jianzhu
J
Chen
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: hemann@mit.edu.
Michael T
MT
Hemann
D000818:Animals; D003520:Cyclophosphamide / Q000627:therapeutic use; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D064593:Heterografts; D006801:Humans; D007113:Immunity, Innate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D009368:Neoplasm Transplantation; D059016:Tumor Microenvironment
D016207:Cytokines; D003520:Cyclophosphamide