Abstract 2820: Macrophages recruited to and function to promote activation of cancer stem cells in response to chemotherapy

Failure of chemoradiotherapy for treating colorectal cancer (CRC) is often caused by the relapse of residual tumor cells that enrich cancer stem cells (CSCs). However, how CSCs are regulated by tumor microenvironment (TME), particularly myeloid derived cells (MDCs), remains unclear. Here, we used the APCMin/+ adenoma model to study the dynamic interaction between MDCs and CSCs in vivo following chemoradiotherapy. Using 3D scanning electronic microscopy, we observed that while proliferating tumor cells were dying following chemoradiotherapy, MDCs or its derivative tumor associated macrophages (TAMs) were recruited to the site where CSCs paired with necroptotic cells. TAMs functioned to promote activation of slow-cycling CSCs. Dissected with single cell RNA-seq, we observed that while proliferating tumor cells were declining following chemotherapy, an increase in MDCs was accompanied with a reduction of immune cells as well as an activation and short-term expansion of initially quiescent CSCs. Depletion of TAMs using a drugs or genetic means resulting in reduced CSCs and attenuated tumorigenesis. Mechanistically, we uncovered that TAM with secreted PGE2 activated Akt and Wnt signaling to promote activation of CSCs. Hence, targeting TAMs will benefit clinical treatment of CRC by reducing drug-resistant CSCs. Note: This abstract was not presented at the meeting. Citation Format: Xi C. He, Linheng Li. Macrophages recruited to and function to promote activation of cancer stem cells in response to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2820.