Tumor-associated macrophages and microglia : double-edged sword in tumor evolvement and invasion

Tumor-associated macrophages (TAMs) are among the most abundant cell types in the tumor microenvironment. TAM infiltration is usually linked to tumor progression, metastasis and poor clinical outcome in most human cancers. These cells sense a wide range of intraand extracellular signals, such as chemokines and growth factors but also disturbances in pH or availability of oxygen. Due to their remarkable plasticity, TAMs can react immediately to these signals and acquire or switch to different phenotypes and activation states accordingly. For the past decade, TAMs have been recognized as a new therapeutic target. Even though diverse monotherapy strategies targeting TAMs have shown limited success, there are many different experimental studies that have shown promising results when approaching TAM subsets in combination with several other treatments, such as chemotherapies. However, our knowledge about the full scope of TAM heterogeneity and function in tumor evolvement and invasion is still lacking. In trying to improve the understanding about the versatile role of TAMs during tumor progression and invasion, several contributions have been made in this thesis. First, we show a novel mechanism whereby the TAM population can be skewed to contain mainly antitumoral M1-like Macrophages. Thus, we show that the overexpression of Semaphorin (SEMA)3A by tumor cells selectively induced the proliferation of M1-like macrophages and decreased the expansion of M2-like macrophages. This resulted in enhanced recruitment and activation of cytotoxic CD8 T lymphocytes and NK cells which in turn inhibited tumor growth. Second, we demonstrate that macrophage-derived Vascular Endothelial Growth Factor (VEGF)-C improved vessel functionality and thereby decreased pulmonary metastasis while tumor-derived VEGF-C increased vessel abnormalization and lung metastasis. Third, we elucidated that Cripto-1 vaccination decreased lung metastasis by inducing a humoral response leading to activated NK cell killing. Finally, we identified that microglia (resident macrophages of the brain) but not bone marrow-derived macrophages (BMDMs) induced Platelet-derived growth factor receptor (PDGFR)B expression on glioma cells and thereby enhanced their migratory capacity. LIST OF SCIENTIFIC 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 A1, De Palma M, Östman A, Andersson J, Rolny C. Guidance Molecule SEMA3A Restricts Tumor Growth by Differently Regulating the Proliferation of Tumor-Associated Macrophages Cancer Res. 2016 Jun 1;76(11):3166-78 II. Wallmann T, Landwehr LS, Squadrito ML, Wallerius M, Agardy D, Bartish M, Hartman J, Bergh J, De Palma M, Rolny C. Macrophage-derived Vascular Endothelial Growth Factor C decreases hematogeneous metastatic dissemination by normalizing the tumor vasculature Manuscript III. Witt K*, Ligtenberg MA*, Conti L, Lanzardo S, Ruiu R, Wallmann T, Tufvesson-Stiller H, Rolny C, Lladser A, Lundqvist A, Cavallo F, Kiessling R. Cripto-1 plasmid DNA vaccination targets metastasis and cancer stem cells in murine mammary carcinoma Cancer Immunol Res. 2018 Aug 24; in press IV. Wallmann T, Zhang XM, Wallerius M, Bolin S, Joly AL, Sobocki C, Leiss L, Jiang Y, Bergh J, Holland EC, Enger P, Andersson J, Swartling F, Miletic H, Uhrbom L, Harris RA, Rolny C. Microglia induce PDGFRB expression in glioma cells to enhance their migratory capacity Accepted, iScience * equal contribution CONTENTS