Exploring mechanisms regulating the heterogeneity of tumor-associated macrophages
Author: Wallerius, Majken
Date: 2018-05-25
Location: Cancer Center Karolinska (CCK) Lecture Hall, R8:00, Karolinska University Hospital, Stockholm
Time: 9.15
Department: Inst för onkologi-patologi / Dept of Oncology-Pathology
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Thesis (2.198Mb)
Abstract
Accumulation of macrophages in the tumor microenvironment is associated to poor prognoses in most human cancers. Tumor-associated macrophages (TAMs) represent a heterogeneous and plastic population of cells that contribute to tumor growth, metastatic dissemination, angiogenesis, and immune suppression. Both recruitment of monocytes from the blood and in situ proliferation contribute to the accumulation of TAMs. During the course of tumor progression, the phenotype of the infiltrating TAMs is changing by influences from other cells, extracellular signal molecules and availability of oxygen and nutrients. Therapeutic targeting of TAMs as a monotherapy has limited success, however, experimental studies show promising results when selectively depleting specific subsets of TAMs or changing the function of the TAM population. Yet, the mechanisms whereby macrophage phenotypes are regulated during tumor growth are still largely unknown.
In this thesis, we investigated mechanisms underlying the dynamic changes in the TAM population observed during tumor growth. In our first study, overexpression of semaphorin 3A induced the proliferation of anti-tumoral macrophages and at the same time reduced the proliferation of pro-tumoral TAMs resulting in accumulation and activation of CD8+ T-cells and NK-cells and restricted tumor growth. In study II, we identified translational regulation of gene expression as an important mechanism regulating the TAM phenotype during tumor growth. By selective inhibition of translational activation, pro-tumoral macrophages were skewed towards an anti-tumoral phenotype. In the third study, we demonstrated a functional difference between macrophages of different ontogeny in a mouse model of glioblastoma. M2-polarized microglia, but not bone-marrow derived macrophages induced the expression of platelet-derived growth factor receptor B (PDGFRB) in glioma cells, enhancing their migratory capacity. In study IV, we showed that Zoledronic acid in combination with interleukin-2 induced the expression of interferon-g by monocytes leading to an up-regulation of TNF-related apoptosis-inducing ligand (TRAIL) on NKcells, inducing their cytotoxicity against tumor cells.
In summary, we describe several mechanisms whereby the TAM phenotype may be regulated i.e translational control of gene expression, regulation of proliferation and ontogeny.
In this thesis, we investigated mechanisms underlying the dynamic changes in the TAM population observed during tumor growth. In our first study, overexpression of semaphorin 3A induced the proliferation of anti-tumoral macrophages and at the same time reduced the proliferation of pro-tumoral TAMs resulting in accumulation and activation of CD8+ T-cells and NK-cells and restricted tumor growth. In study II, we identified translational regulation of gene expression as an important mechanism regulating the TAM phenotype during tumor growth. By selective inhibition of translational activation, pro-tumoral macrophages were skewed towards an anti-tumoral phenotype. In the third study, we demonstrated a functional difference between macrophages of different ontogeny in a mouse model of glioblastoma. M2-polarized microglia, but not bone-marrow derived macrophages induced the expression of platelet-derived growth factor receptor B (PDGFRB) in glioma cells, enhancing their migratory capacity. In study IV, we showed that Zoledronic acid in combination with interleukin-2 induced the expression of interferon-g by monocytes leading to an up-regulation of TNF-related apoptosis-inducing ligand (TRAIL) on NKcells, inducing their cytotoxicity against tumor cells.
In summary, we describe several mechanisms whereby the TAM phenotype may be regulated i.e translational control of gene expression, regulation of proliferation and ontogeny.
List of papers:
I. Wallerius M, Wallmann T, Bartish M, Östling J, Mezheyeuski A, Tobin NP, Nygren E, Pangigadde P, Pellegrini P, Squadrito ML, Pontén F, Hartman J, Bergh J, De Milito A, De Palma M, Östman A, Andersson J, Rolny C. Guidance Molecule SEMA3A Restricts Tumor Growth by Differentially Regulating the Proliferation of Tumor-Associated Macrophages. Cancer Res. 2016 Jun 1;76(11):3166-78.
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II. Bartish M, Wallerius M, Wallmann T, Masvidal L, Liu H, Joly AL, van Hoef V, Bergh J, Hartman J, Andersson J, Rolny C, Larsson O. RNA Translational Control of the Tumor-Associated Macrophage Phenotype. [Manuscript]
III. Wallmann T, Zhang XM, Wallerius M, Bolin S, Joly AL, Sobocki C, Leiss L, Jiang Y, Bergh J, Andersson J, Holland E, Enger P, Swartling F, Uhrbom L, Miletic H, Harris R, Rolny, C. Pro-Angiogenic microglia-induced expression of platelet-derived growth factor receptor beta in glioma cells promotes their migratory capacity. [Submitted]
IV. Sarhan D, D'Arcy P, Wennerberg E, Lidén M, Hu J, Winqvist O, Rolny C, Lundqvist A. Activated monocytes augment TRAIL-mediated cytotoxicity by human NK cells through release of IFN-γ. Eur J Immunol. 2013 Jan;43(1):249-57.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Wallerius M, Wallmann T, Bartish M, Östling J, Mezheyeuski A, Tobin NP, Nygren E, Pangigadde P, Pellegrini P, Squadrito ML, Pontén F, Hartman J, Bergh J, De Milito A, De Palma M, Östman A, Andersson J, Rolny C. Guidance Molecule SEMA3A Restricts Tumor Growth by Differentially Regulating the Proliferation of Tumor-Associated Macrophages. Cancer Res. 2016 Jun 1;76(11):3166-78.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Bartish M, Wallerius M, Wallmann T, Masvidal L, Liu H, Joly AL, van Hoef V, Bergh J, Hartman J, Andersson J, Rolny C, Larsson O. RNA Translational Control of the Tumor-Associated Macrophage Phenotype. [Manuscript]
III. Wallmann T, Zhang XM, Wallerius M, Bolin S, Joly AL, Sobocki C, Leiss L, Jiang Y, Bergh J, Andersson J, Holland E, Enger P, Swartling F, Uhrbom L, Miletic H, Harris R, Rolny, C. Pro-Angiogenic microglia-induced expression of platelet-derived growth factor receptor beta in glioma cells promotes their migratory capacity. [Submitted]
IV. Sarhan D, D'Arcy P, Wennerberg E, Lidén M, Hu J, Winqvist O, Rolny C, Lundqvist A. Activated monocytes augment TRAIL-mediated cytotoxicity by human NK cells through release of IFN-γ. Eur J Immunol. 2013 Jan;43(1):249-57.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Rolny, Charlotte
Co-supervisor: Lundqvist, Andreas; Östman, Arne
Issue date: 2018-05-03
Rights:
Publication year: 2018
ISBN: 978-91-7831-011-1
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