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

• Published in: PloS one Vol. 12; no. 10; p. 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: Journal Article
• Language: English
• Published: United States Public Library of Science 30.10.2017; Public Library of Science (PLoS)
• 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; Tumors; γ-Interferon; Canada
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0187262

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.