Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells.
Tumor-associated macrophages (TAMs), the most abundant immunosuppressive cells in the tumor microenvironment, originate from blood monocytes and exhibit an IL-10(high)IL-12(low) M2 profile. The factors involved in TAM generation remain unidentified. We identify here leukemia inhibitory factor (LIF) and IL-6 as tumor microenvironmental factors that can promote TAM generation. Ovarian cancer ascites switched monocyte differentiation into TAM-like cells that exhibit most ovarian TAM functional and phenotypic characteristics. Ovarian cancer ascites contained high concentrations of LIF and IL-6. Recombinant LIF and IL-6 skew monocyte differentiation into TAM-like cells by enabling monocytes to consume monocyte-colony-stimulating factor (M-CSF). Depletion of LIF, IL-6, and M-CSF in ovarian cancer ascites suppressed TAM-like cell induction. We extended these observations to different tumor-cell line supernatants. In addition to revealing a new tumor-escape mechanism associated with TAM generation via LIF and IL-6, these findings offer novel therapeutic perspectives to subvert TAM-induced immunosuppression and hence improve T-cell-based antitumor immunotherapy efficacy.
Duluc
Dorothée
D
Inserm, U564, Equipe Avenir, Angers, France.
Delneste
Yves
Y
Tan
Fang
F
Moles
Marie-Pierre
MP
Grimaud
Linda
L
Lenoir
Julien
J
Preisser
Laurence
L
Anegon
Ignacio
I
Catala
Laurent
L
Ifrah
Norbert
N
Descamps
Philippe
P
Gamelin
Erick
E
Gascan
Hugues
H
Hebbar
Mohamed
M
Jeannin
Pascale
P
D001201:Ascites; D002454:Cell Differentiation; D003115:Colony-Stimulating Factors; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D053605:Leukemia Inhibitory Factor / Q000502:physiology*; D008264:Macrophages / Q000166:cytology*; D009000:Monocytes / Q000166:cytology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured; D019139:Tumor Escape
D003115:Colony-Stimulating Factors; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor