Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment.

Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment.

Cancer Res. 2013 Feb 22;

Authors: Dijkgraaf EM, Heusinkveld M, Tummers B, Vogelpoel LT, Goedemans R, Jha V, Nortier JW, Welters MJ, Kroep JR, van der Burg SH

Abstract
Current therapy of gynecological malignancies consists of platinum-containing chemotherapy. Resistance to therapy is associated with increased levels of interleukin-6 (IL-6) and prostaglandin E2 (PGE(2)), two inflammatory mediators known to skew differentiation of monocytes to tumor-promoting M2 macrophages. We investigated the impact of cisplatin and carboplatin on 10 different cervical and ovarian cancer cell lines as well as on the ability of the tumor cells to affect the differentiation and function of co-cultured monocytes in vitro. Treatment with cisplatin or carboplatin increased the potency of tumor cell lines to induce IL-10-producing M2 macrophages which displayed increased levels of activated signal transducer and activator of transcription-3 (STAT3) due to tumor-produced IL-6 as well as decreased levels of activated STAT1 and STAT6 related to the PGE(2)-production of tumor cells. Blockade of canonical NF?B signaling showed that the effect of the chemotherapy was abrogated, preventing the subsequent increased production of PGE(2) and/or IL-6 by the tumor cell lines. Treatment with the cyclooxygenase (COX)-inhibitor indomethacin and/or the clinical monoclonal antibody against IL-6 receptor (IL-6R), tocilizumab, prevented M2-differentiation. Importantly, no correlation existed between the production of PGE(2) or IL-6 by cancer cells and their resistance to chemotherapy-induced cell death, indicating that other mechanisms underlie the reported chemoresistance of tumors producing these factors. Our data suggests that a chemotherapy-mediated increase in tumor-promoting M2 macrophages may form an indirect mechanism for chemoresistance. Hence, concomitant therapy with COX-inhibitors and/or IL-6R antibodies might increase the clinical effect of platinum-based chemotherapy in otherwise resistant tumors.

PMID: 23436796 [PubMed - as supplied by publisher]

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