Chemotherapy enriches for pro-inflammatory macrophage phenotypes that support cancer stem-like cells and disease progression in ovarian cancer.

Abstract

High-grade serous ovarian cancer (HGSOC) remains a poorly understood disease with a high mortality rate. While most patients respond to cytotoxic therapies, a majority will experience recurrence. This may be due to a minority of drug resistant cancer stem-like cells (CSCs) that survive chemotherapy and are capable of repopulating heterogenous tumors. It remains unclear how CSCs are supported in the tumor microenvironment (TME) particularly during chemotherapy exposure. Tumor associated macrophages (TAMs) make up half of the immune population of the ovarian TME and are known to support CSCs and contribute to cancer progression. TAMs are plastic cells that alter their phenotype in response to environmental stimuli and thus may influence CSC maintenance during chemotherapy. Given the plasticity of TAMs we studied the effects of carboplatin on macrophage phenotypes using both THP-1- and peripheral blood mononuclear cell (PBMC)- derived macrophages and whether this supports CSCs and ovarian cancer progression following treatment. We found that carboplatin exposure induces an M1-like pro-inflammatory phenotype that promotes SOX2 expression, spheroid formation, and CD117+ ovarian CSCs, and that macrophage-secreted CCL2/MCP-1 is at least partially responsible for this effect. Depletion of TAMs during carboplatin exposure results in fewer CSCs and prolonged survival in a xenograft model of ovarian cancer. This study supports a role for platinum-based chemotherapies in promoting a transient pro-inflammatory M1-like TAM that enriches for CSCs during treatment. Improving our understanding of TME responses to cytotoxic drugs and identifying novel mechanisms of CSC maintenance will enable the development of better therapeutic strategies for HGSOC.