Imprime PGG-Mediated Anti-Cancer Immune Activation Requires Immune Complex Formation

Autor: Ben J. Harrison, Nandita Bose, Xiaohong Qiu, Kyle S. Michel, Jeremy R. Graff, Richard Walsh, Mariana I. Nelson, Nadine R. Ottoson, Adria Jonas, Keith B. Gorden, Steven M. Leonardo, Michael E. Danielson, Kathleen E. Ertelt, Peter Maimonis, Anissa S.H. Chan, Myra L. Patchen
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
beta-Glucans
Neutrophils
Physiology
Complement System
lcsh:Medicine
Complement receptor
Antigen-Antibody Complex
Immune Complex
Biochemistry
Monocytes
White Blood Cells
Spectrum Analysis Techniques
Animal Cells
Immune Physiology
Medicine and Health Sciences
Enzyme-Linked Immunoassays
lcsh:Science
Complement Activation
Multidisciplinary
Immune System Proteins
Flow Cytometry
Immune complex
Cell biology
Spectrophotometry
Cytophotometry
Cellular Types
Research Article
Immune Cells
Immunology
Macrophage-1 Antigen
Antineoplastic Agents
Biology
Immune complex formation
Research and Analysis Methods
Antibodies
03 medical and health sciences
Classical complement pathway
Immune system
Humans
Immunoassays
Innate immune system
Blood Cells
lcsh:R
Receptors
IgG
Biology and Life Sciences
Proteins
Cell Biology
Immunity
Innate
Complement system
030104 developmental biology
HEK293 Cells
Immune System
Immunologic Techniques
iC3b
lcsh:Q
Zdroj: PLoS ONE
PLoS ONE, Vol 11, Iss 11, p e0165909 (2016)
ISSN: 1932-6203
Popis: Imprime PGG (Imprime), an intravenously-administered, soluble β-glucan, has shown compelling efficacy in multiple phase 2 clinical trials with tumor targeting or anti-angiogenic antibodies. Mechanistically, Imprime acts as pathogen-associated molecular pattern (PAMP) directly activating innate immune effector cells, triggering a coordinated anti-cancer immune response. Herein, using whole blood from healthy human subjects, we show that Imprime-induced anti-cancer functionality is dependent on immune complex formation with naturally-occurring, anti-β glucan antibodies (ABA). The formation of Imprime-ABA complexes activates complement, primarily via the classical complement pathway, and is opsonized by iC3b. Immune complex binding depends upon Complement Receptor 3 and Fcg Receptor IIa, eliciting phenotypic activation of, and enhanced chemokine production by, neutrophils and monocytes, enabling these effector cells to kill antibody-opsonized tumor cells via the generation of reactive oxygen species and antibody-dependent cellular phagocytosis. Importantly, these innate immune cell changes were not evident in subjects with low ABA levels but could be rescued with exogenous ABA supplementation. Together, these data indicate that pre-existing ABA are essential for Imprime-mediated anti-cancer immune activation and suggest that pre-treatment ABA levels may provide a plausible patient selection biomarker to delineate patients most likely to benefit from Imprime-based therapy.
Databáze: OpenAIRE
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