title: Loss of prolyl hydroxylase-2 in myeloid cells and T-lymphocytes impairs tumor development.
abstract: The tumor microenvironment plays a pivotal role during cancer development and progression. The balance between suppressive and cytotoxic responses of the tumor immune microenvironment has been shown to have a direct effect on the final outcome in various human and experimental tumors. Recently, we demonstrated that the oxygen sensor HIF-prolyl hydroxylase-2 (PHD2) plays a detrimental role in tumor cells, stimulating systemic growth and metastasis in mice. In our current study, we show that the conditional ablation of PHD2 in the hematopoietic system also leads to reduced tumor volume, intriguingly generated by an imbalance between enhanced cell death and improved proliferation of tumor cells. This effect seems to rely on the overall downregulation of protumoral as well as antitumoral cytokines. Using different genetic approaches, we were able to confine this complex phenotype to the crosstalk of PHD2-deficient myeloid cells and T-lymphocytes. Taken together, our findings reveal a multifaceted role for PHD2 in several hematopoietic lineages during tumor development and might have important implications for the development of tumor therapies in the future.
authors.affiliation: Emmy Noether Research Group, University of Technology, Dresden, Germany; Institute of Pathology, University of Technology Dresden, Dresden, Germany.
authors.forename: Soulafa
authors.initials: S
authors.lastname: Mamlouk
authors.forename: Joanna
authors.initials: J
authors.lastname: Kalucka
authors.forename: Rashim Pal
authors.initials: RP
authors.lastname: Singh
authors.forename: Kristin
authors.initials: K
authors.lastname: Franke
authors.forename: Antje
authors.initials: A
authors.lastname: Muschter
authors.forename: Anika
authors.initials: A
authors.lastname: Langer
authors.forename: Christiane
authors.initials: C
authors.lastname: Jakob
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
authors.forename: Gustavo B
authors.initials: GB
authors.lastname: Baretton
authors.forename: Ben
authors.initials: B
authors.lastname: Wielockx
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002465:Cell Movement; D049109:Cell Proliferation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000502:physiology*; D007124:Immunoenzyme Techniques; D019426:Integrases / Q000378:metabolism; D008546:Melanoma, Experimental / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D014408:Biomarkers, Tumor; D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D019426:Integrases; D012333:RNA, Messenger; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C497443:Hif1a protein, mouse; C490189:Egln1 protein, mouse; C045073:Cre recombinase
keywords: cytokines; prolyl hydroxylase-2; tumor-associated immune cells