Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy

Russell Hughes, Bin-Zhi Qian, Charlotte Rowan, Munitta Muthana, Ioanna Keklikoglou, Oakley C Olson, Simon Tazzyman, Sarah Danson, Christina Addison, Mark Clemons, Ana Maria Gonzalez-Angulo, Johanna A Joyce, Michele De Palma, Jeffrey W. Pollard, Claire E Lewis

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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+TIE2HiCXCR4Hi) 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.

Original languageEnglish
Pages (from-to)3479-3491
Number of pages13
JournalCancer Research
Volume75
Issue number17
Early online date12 Aug 2015
DOIs
Publication statusPublished - 1 Sept 2015

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