Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population.
Tumor-associated macrophages (TAM) are exposed to multiple microenvironmental cues in tumors, which collaborate to endow these cells with protumoral activities. Hypoxia, caused by an imbalance in oxygen supply and demand because of a poorly organized vasculature, is often a prominent feature in solid tumors. However, to what extent tumor hypoxia regulates the TAM phenotype in vivo is unknown. Here, we show that the myeloid infiltrate in mouse lung carcinoma tumors encompasses two morphologically distinct CD11b(hi)F4/80(hi)Ly6C(lo) TAM subsets, designated as MHC-II(lo) and MHC-II(hi) TAM, both of which were derived from tumor-infiltrating Ly6C(hi) monocytes. MHC-II(lo) TAM express higher levels of prototypical M2 markers and reside in more hypoxic regions. Consequently, MHC-II(lo) TAM contain higher mRNA levels for hypoxia-regulated genes than their MHC-II(hi) counterparts. To assess the in vivo role of hypoxia on these TAM features, cancer cells were inoculated in prolyl hydroxylase domain 2 (PHD2)-haplodeficient mice, resulting in better-oxygenated tumors. Interestingly, reduced tumor hypoxia did not alter the relative abundance of TAM subsets nor their M2 marker expression, but specifically lowered hypoxia-sensitive gene expression and angiogenic activity in the MHC-II(lo) TAM subset. The same observation in PHD2(+/+) → PHD2(+/-) bone marrow chimeras also suggests organization of a better-oxygenized microenvironment. Together, our results show that hypoxia is not a major driver of TAM subset differentiation, but rather specifically fine-tunes the phenotype of M2-like MHC-II(lo) TAM.
Authors' Affiliations: Laboratory of Myeloid Cell Immunology, VIB; Laboratory of Cellular and Molecular Immunology; Cell Differentiation Unit, Diabetes Research Centre, Vrije Universiteit Brussel; Biomedical Magnetic Resonance Unit, U.C. Louvain, Brussels; Laboratory of Molecular Oncology and Angiogenesis; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB; and Experimental Medicine and Endocrinology, Department of Experimental Medicine, K.U. Leuven, Leuven, Belgium.
Damya
D
Laoui
Eva
E
Van Overmeire
Giusy
G
Di Conza
Chiara
C
Aldeni
Jiri
J
Keirsse
Yannick
Y
Morias
Kiavash
K
Movahedi
Isabelle
I
Houbracken
Elio
E
Schouppe
Yvon
Y
Elkrim
Oussama
O
Karroum
Bénédicte
B
Jordan
Peter
P
Carmeliet
Conny
C
Gysemans
Patrick
P
De Baetselier
Massimiliano
M
Mazzone
Jo A
JA
Van Ginderachter
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D059467:Transcriptome