title: Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses.
abstract: 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 seems 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 show that targeting tumor-infiltrating macrophages (TAM) and inflammatory monocytes by inhibiting either the myeloid cell receptors colony-stimulating factor-1 receptor (CSF1R) or chemokine (C-C motif) receptor 2 (CCR2) decreases the number of tumor-initiating cells (TIC) 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 TAMs can effectively overcome therapeutic resistance mediated by TICs.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Mitchem
authors.forename: Donal J
authors.initials: DJ
authors.lastname: Brennan
authors.forename: Brett L
authors.initials: BL
authors.lastname: Knolhoff
authors.forename: Brian A
authors.initials: BA
authors.lastname: Belt
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhu
authors.forename: Dominic E
authors.initials: DE
authors.lastname: Sanford
authors.forename: Larisa
authors.initials: L
authors.lastname: Belaygorod
authors.forename: Danielle
authors.initials: D
authors.lastname: Carpenter
authors.forename: Lynne
authors.initials: L
authors.lastname: Collins
authors.forename: David
authors.initials: D
authors.lastname: Piwnica-Worms
authors.forename: Stephen
authors.initials: S
authors.lastname: Hewitt
authors.forename: Girish Mallya
authors.initials: GM
authors.lastname: Udupi
authors.forename: William M
authors.initials: WM
authors.lastname: Gallagher
authors.forename: Craig
authors.initials: C
authors.lastname: Wegner
authors.forename: Brian L
authors.initials: BL
authors.lastname: West
authors.forename: Andrea
authors.initials: A
authors.lastname: Wang-Gillam
authors.forename: Peter
authors.initials: P
authors.lastname: Goedegebuure
authors.forename: David C
authors.initials: DC
authors.lastname: Linehan
authors.forename: David G
authors.initials: DG
authors.lastname: DeNardo
mesh_terms: D000818:Animals; D002450:Cell Communication; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D000093542:Gemcitabine
chemical_list: D054390:Receptors, CCR2; D050796:STAT3 Transcription Factor; D003841:Deoxycytidine; D016186:Receptor, Macrophage Colony-Stimulating Factor; D000093542:Gemcitabine