Modulation of macrophage antitumor potential by apoptotic lymphoma cells.
In aggressive non-Hodgkin's lymphoma (NHL), constitutive apoptosis of a proportion of the tumor cell population can promote net tumor growth. This is associated with the accumulation of tumor-associated macrophages (TAMs) that clear apoptotic cells and exhibit pro-oncogenic transcriptional activation profiles characteristic of reparatory, anti-inflammatory and angiogenic programs. Here we consider further the activation status of these TAMs. We compare their transcriptomic profile with that of a range of other macrophage types from various tissues noting especially their expression of classically activated (IFN-γ and LPS) gene clusters - typically antitumor - in addition to their previously described protumor phenotype. To understand the impact of apoptotic cells on the macrophage activation state, we cocultured apoptotic lymphoma cells with classically activated macrophages (M(IFN-γ/LPS), also known as M1, macrophages). Although untreated and M(IFN-γ/LPS)macrophages were able to bind apoptotic lymphoma cells equally well, M(IFN-γ/LPS)macrophages displayed enhanced ability to phagocytose them. We found that direct exposure of M(IFN-γ/LPS)macrophages to apoptotic lymphoma cells caused switching towards a protumor activation state (often referred to as M2-like) with concomitant inhibition of antitumor activity that was a characteristic feature of M(IFN-γ/LPS)macrophages. Indeed, M(IFN-γ/LPS)macrophages exposed to apoptotic lymphoma cells displayed increased lymphoma growth-promoting activities. Antilymphoma activity by M(IFN-γ/LPS)macrophages was mediated, in part, by galectin-3, a pleiotropic glycoprotein involved in apoptotic cell clearance that is strongly expressed by lymphoma TAMs but not lymphoma cells. Intriguingly, aggressive lymphoma growth was markedly impaired in mice deficient in galectin-3, suggesting either that host galectin-3-mediated antilymphoma activity is required to sustain net tumor growth or that additional functions of galectin-3 drive key oncogenic mechanisms in NHL. These findings have important implications for anticancer therapeutic approaches aimed at polarizing macrophages towards an antitumor state and identify galectin-3 as a potentially important novel target in aggressive NHL.
Medical Research Council (MRC) Center for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
Jorine J L P
JJLP
Voss
Medical Research Council (MRC) Center for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
Catriona A
CA
Ford
Medical Research Council (MRC) Center for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
Sofia
S
Petrova
Medical Research Council (MRC) Center for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
Lynsey
L
Melville
Medical Research Council (MRC) Center for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
Margaret
M
Paterson
Medical Research Council (MRC) Center for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
John D
JD
Pound
Medical Research Council (MRC) Center for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
Pam
P
Holland
The Roslin Institute, R(D)SVS, University of Edinburgh, Easter Bush EH25 9RG, UK.
Bruno
B
Giotti
The Roslin Institute, R(D)SVS, University of Edinburgh, Easter Bush EH25 9RG, UK.
Tom C
TC
Freeman
Medical Research Council (MRC) Center for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
Christopher D
CD
Gregory
D000818:Animals; D017209:Apoptosis; D018920:Coculture Techniques; D005260:Female; D037502:Galectin 3 / Q000378:metabolism / Q000502:physiology*; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology / Q000503:physiopathology*; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D010587:Phagocytosis; D059467:Transcriptome
D037502:Galectin 3