Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy.
Tumor relapse after chemotherapy-induced regression is a major clinical problem, because it often involves inoperable metastatic disease. Tumor-associated macrophages (TAM) are known to limit the cytotoxic effects of chemotherapy in preclinical models of cancer. Here, we report that an alternatively activated (M2) subpopulation of TAMs (MRC1(+)TIE2(Hi)CXCR4(Hi)) accumulate around blood vessels in tumors after chemotherapy, where they promote tumor revascularization and relapse, in part, via VEGF-A release. A similar perivascular, M2-related TAM subset was present in human breast carcinomas and bone metastases after chemotherapy. Although a small proportion of M2 TAMs were also present in hypoxic tumor areas, when we genetically ablated their ability to respond to hypoxia via hypoxia-inducible factors 1 and 2, tumor relapse was unaffected. TAMs were the predominant cells expressing immunoreactive CXCR4 in chemotherapy-treated mouse tumors, with the highest levels expressed by MRC1(+) TAMs clustering around the tumor vasculature. Furthermore, the primary CXCR4 ligand, CXCL12, was upregulated in these perivascular sites after chemotherapy, where it was selectively chemotactic for MRC1(+) TAMs. Interestingly, HMOX-1, a marker of oxidative stress, was also upregulated in perivascular areas after chemotherapy. This enzyme generates carbon monoxide from the breakdown of heme, a gas known to upregulate CXCL12. Finally, pharmacologic blockade of CXCR4 selectively reduced M2-related TAMs after chemotherapy, especially those in direct contact with blood vessels, thereby reducing tumor revascularization and regrowth. Our studies rationalize a strategy to leverage chemotherapeutic efficacy by selectively targeting this perivascular, relapse-promoting M2-related TAM cell population.
Department of Oncology, University of Sheffield Medical School, Sheffield, United Kingdom.
Russell
R
Hughes
MRC Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
Bin-Zhi
BZ
Qian
Department of Oncology, University of Sheffield Medical School, Sheffield, United Kingdom.
Charlotte
C
Rowan
Department of Oncology, University of Sheffield Medical School, Sheffield, United Kingdom.
Munitta
M
Muthana
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Ioanna
I
Keklikoglou
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Oakley C
OC
Olson
Department of Oncology, University of Sheffield Medical School, Sheffield, United Kingdom.
Simon
S
Tazzyman
Department of Oncology, University of Sheffield Medical School, Sheffield, United Kingdom.
Sarah
S
Danson
Cancer Therapeutics Program, Ottawa Hospital Research Institute, and Department of Medicine, University of Ottawa, Ontario, Canada.
Christina
C
Addison
Cancer Therapeutics Program, Ottawa Hospital Research Institute, and Department of Medicine, University of Ottawa, Ontario, Canada.
Mark
M
Clemons
Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Ana Maria
AM
Gonzalez-Angulo
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Johanna A
JA
Joyce
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Michele
M
De Palma
MRC Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, United Kingdom. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York.
Jeffrey W
JW
Pollard
Department of Oncology, University of Sheffield Medical School, Sheffield, United Kingdom. claire.lewis@sheffield.ac.uk.
Claire E
CE
Lewis
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000008:administration & dosage; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A; D013629:Tamoxifen