TTI-621 (SIRPαFc), a CD47-blocking cancer immunotherapeutic, triggers phagocytosis of lymphoma cells by multiple polarized macrophage subsets

Tumor-associated macrophages (TAMs) are heterogeneous and can adopt a spectrum of activation states between pro-inflammatory and pro-tumorigenic in response to the microenvironment. We have previously shown that TTI-621, a soluble SIRPαFc fusion protein that blocks the CD47 "do-not-eat" si...

Full description

Saved in:

Bibliographic Details
Published in:	PloS one 2017-10, Vol.12 (10), p.e0187262-e0187262
Main Authors:	Lin, Gloria H Y, Chai, Vien, Lee, Vivian, Dodge, Karen, Truong, Tran, Wong, Mark, Johnson, Lisa D, Linderoth, Emma, Pang, Xinli, Winston, Jeff, Petrova, Penka S, Uger, Robert A, Viller, Natasja N
Format:	Article
Language:	eng
Subjects:	Animals Antigens, Differentiation - physiology Cancer Cancer cells Cell activation Cell Line, Tumor Cell Polarity Cell surface Cytokines Cytokines - biosynthesis Female Fusion protein Genetic aspects Genotype & phenotype Humans Immunoglobulin Fc Fragments - physiology Immunophenotyping Inflammation Interferon Interleukin 10 Interleukin 4 Lipopolysaccharides Lymphoma Lymphoma, Large B-Cell, Diffuse - immunology Macrophages Macrophages - immunology Medical prognosis Membrane proteins Mice Mice, Hairless Phagocytes Phagocytosis Phagocytosis - physiology Physiological aspects Proteins Receptors Receptors, Immunologic - physiology Rodents Surface markers Tumor cells γ-Interferon
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Tumor-associated macrophages (TAMs) are heterogeneous and can adopt a spectrum of activation states between pro-inflammatory and pro-tumorigenic in response to the microenvironment. We have previously shown that TTI-621, a soluble SIRPαFc fusion protein that blocks the CD47 "do-not-eat" signal, promotes tumor cell phagocytosis by IFN-γ-primed macrophages. To assess the impact of CD47 blockade on diverse types of macrophages that are found within the tumor microenvironment, six different polarized human macrophage subsets (M(-), M(IFN-γ), M(IFN-γ+LPS), M(IL-4), M(HAGG+IL-1β), M(IL-10 + TGFβ)) with distinct cell surface markers and cytokine profiles were generated. Blockade of CD47 using TTI-621 significantly increased phagocytosis of lymphoma cells by all macrophage subsets, with M(IFN-γ), M(IFN-γ+LPS) and M(IL-10 + TGFβ) macrophages having the highest phagocytic response. TTI-621-mediated phagocytosis involves macrophage expression of both the low- and high-affinity Fcγ receptors II (CD32) and I (CD64), respectively. Moreover, macrophages with lower phagocytic capabilities (M(-), M(IL-4), M(HAGG+IL-1β)) could readily be re-polarized into highly phagocytic macrophages using various cytokines or TLR agonists. In line with the in vitro study, we further demonstrate that TTI-621 can trigger phagocytosis of tumor cells by diverse subsets of isolated mouse TAMs ex vivo. These data suggest that TTI-621 may be efficacious in triggering the destruction of cancer cells by a diverse population of TAMs found in vivo and support possible combination approaches to augment the activity of CD47 blockade.
ISSN:	1932-6203 1932-6203