Cancer-Associated Fibroblasts Exposed to High-Dose Ionizing Radiation Promote M2 Polarization of Macrophages, Which Induce Radiosensitivity in Cervical Cancer

SIMPLE SUMMARY: Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) in the tumor microenvironment are critical factors in the curative effects of cancer therapies. The aim of our study was to explore the interactions between TAMs and CAFs in the context of ionizing radiation. We confirmed that M2 macrophages correlate with poor prognosis and induce radioresistance in cervical cancer. M2 polarization was increased after high-dose IR in both mouse models and patients with cervical cancer. M2 macrophage contents were increased in CAF-positive regions in patients with cervical cancer who relapsed after receiving radical radiotherapy. In addition, high-dose irradiated CAFs promote macrophage M2 polarization in cervical cancer through the secretion of chemokine (C-C motif) ligand 2 (CCL2). Our data provide a new insight into the relation between CAFs and TAMs under IR, which is of significance for further exploration of the mechanism of radioresistance in cervical cancer. ABSTRACT: Radiotherapy, including brachytherapy, is a major therapeutic regimen for cervical cancer. Radioresistance is a decisive factor in radiation treatment failure. Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) in the tumor microenvironment are critical factors in the curative effects of cancer therapies. However, the interactions between TAMs and CAFs in the context of ionizing radiation are not fully understood. This study was undertaken to investigate whether M2 macrophages induce radioresistance in cervical cancer and to explore the TAMs’ phenotypic transformation after IR and its underlying mechanisms. The radioresistance of cervical cancer cells was enhanced after being co-cultured with M2 macrophages. TAMs tended to undergo M2 polarization after high-dose irradiation, which was strongly associated with CAFs in both mouse models and patients with cervical cancer. Additionally, cytokine and chemokine analysis was performed to find that high-dose irradiated CAFs promoted macrophage polarization towards the M2 phenotype through chemokine (C-C motif) ligand 2. Collectively, our results highlight the crucial role that high-dose irradiated CAFs play in the regulation of M2 phenotype polarization, which ultimately induces radioresistance in cervical cancer.