Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy

Abstract

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.

The impact of hypoxia on tumor-associated macrophages

“…Macrophages recruited to clear the damaged tissue might counterproductively be skewed within these hypoxic areas towards a tumor-promoting phenotype, contributing to tumor relapse (Figure 1). Moreover, a specific subset of M2-type macrophages (MRC1 + TIE2 hi CXCR4 hi ) accumulates in perivascular regions following chemotherapy and accounts for high VEGFA expression in these regions (78). Thus, it is conceivable that these macrophages might initiate an angiogenic response that restores tumor vascularization.…”

Circulating tumor cell interactions with macrophages: implications for biology and treatment

“…Small cell lung cancer (SCLC) accounts for approximately 15% of lung cancers and represents an aggressive tumor with high numbers of CTCs which are involved in early dissemination (7). The unique properties of CTCs of ED-SCLC allowed us to expand six cell lines from blood samples of patients with metastatic disease in vitro (BHGc7, 10,16,26,27 and UHGc5) and to study their cell biologic characteristics and interaction with normal cell populations of the tumor microenvironment (8). SCLC disseminates rapidly such representing a suitable tumor model of both cancer spread and development of general chemoresistance.…”

“…Hematopoietic cells are recruited to most tumors and one group, the TAMs, can constitute a large portion of the tumor mass (13,14). Macrophages produce an array of cytokines, chemokines, polypeptide growth factors, hormones, matrix remodeling proteases and metabolites, many of which possess tumor-promoting and tumorprotecting activities (15)(16)(17). For many solid tumor types, high densities of cells expressing macrophage-associated markers have generally been found to associate with poor clinical outcome (18)(19)(20).…”

The endocrine influence on the bone microenvironment in early breast cancer

“…Tumour-associated macrophages (TAMs) are also able to limit the effect of anti-cancer therapies by associating with tumour blood vessels and promoting revascularization after chemotherapy in both primary breast tumours and bone metastases (Hughes et al 2015). In this study, TAMS were attracted to these sites by the interaction of tumour expressed CXCL12 and TAM expressed CXCR4.…”