Abstract LB-168: Perivascular, CXCR4-expressing macrophages in tumors promote relapse following chemotherapy

Abstract

Abstract The relapse of cancer after frontline therapies like chemotherapy is a major clinical problem as tumors often grow back at the site of surgical removal and/or as metastases. Tumor-associated macrophages (TAMs) are a major cellular component of both primary and metastatic tumors, and promote such key processes in tumor progression as angiogenesis, immunosuppression, invasion, and metastasis. Gene expression profiling and immunostaining studies have identified both classically (M1) and alternatively (M2) activated TAMs in human and mouse tumors. Heavily M2-skewed TAMs - those expressing the angiopoietin receptor, TIE2 - have been shown to be important for angiogenesis and immunosuppression in mouse tumors. Moreover, high levels of TAMs expressing another M2 marker, CD163, correlate with poor prognosis in various forms of human cancer. TAMs have been shown recently to reduce the sensitivity of mouse mammary tumors to cytotoxic agents like paclitaxel (PTX) and doxorubicin. Here, we report on our use of various mouse tumor models to investigate the role of TAMs in tumor relapse after chemotherapy. Our studies show that a distinct subset of M2-skewed, CXCR4hi VEGF+ TAMs cluster around blood vessels after administration of various cytotoxic agents. This correlated with increased tumor CXCL12 levels - and the selective depletion of this perivascular TAM subset, using the CXCR4 antagonist, AMD3100 (Plerixafor), revealed an important role for these cells in driving revascularisation and regrowth in post-chemotherapy tumors. Additionally, adoptive transfer of this TAM subset into tumor-bearing mice after chemotherapy accelerated tumor regrowth. No such effect was seen with non-M2 skewed TAMs isolated from the same tumors. These studies suggest that combining chemotherapy with inhibitors of the CXCL12-CXCR4 axis could delay tumor relapse in cancer patients. Citation Format: Claire E. Lewis. Perivascular, CXCR4-expressing macrophages in tumors promote relapse following chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-168. doi:10.1158/1538-7445.AM2014-LB-168