Targeting tumor-infiltrating macrophages decreases tumor-Initiating cells, relieves immunosuppression and improves chemotherapeutic response
Menée sur des lignées cellulaires et à l'aide de modèles murins, cette étude met en évidence l'intérêt de cibler les macrophages infiltrant les tumeurs, à l'aide d'inhibiteurs de CSF1R ou de CCR2, pour réduire le nombre de cellules souches dans les tumeurs de pancréas
Tumor-infiltrating immune cells can promote chemoresistance and metastatic spread in aggressive tumors. Consequently, the type and quality of immune responses present in the neoplastic stroma are highly predictive of patient outcome in several cancer types. In addition to host immune responses, intrinsic tumor cell activities that mimic stem cell properties have been linked to chemoresistance, metastatic dissemination and the induction of immune suppression. Cancer stem cells are far from a static cell population; rather, their presence appears to be controlled by highly dynamic processes that are dependent on cues from the tumor stroma. However, the impact immune responses have on tumor stem cell differentiation or expansion is not well understood. In this study, we demonstrate that targeting tumor-infiltrating macrophages and inflammatory monocytes by inhibiting either the myeloid cell receptors CSF1R or CCR2 decreases the number of tumor-initiating cells in pancreatic tumors. Targeting CCR2 or CSF1R improves chemotherapeutic efficacy, inhibits metastasis and increases antitumor T-cell responses. Tumor-educated macrophages also directly enhanced the tumor-initiating capacity of pancreatic tumor cells by activating the transcription factor STAT3, thereby facilitating macrophage-mediated suppression of CD8+ T lymphocytes. Together, our findings show how targeting tumor-infiltrating macrophages can effectively overcome therapeutic resistance mediated by tumor-initiating cells.