Polarization and β-Glucan Reprogram Immunomodulatory Metabolism in Human Macrophages and Ex Vivo in Human Lung Cancer Tissues.

Autor:	Fan TW; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY; twmfan@gmail.com andrew.lane@uky.edu.; Markey Cancer Center, University of Kentucky, Lexington, KY; and.; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY., Daneshmandi S; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY., Cassel TA; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY., Uddin MB; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY., Sledziona J; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY., Thompson PT; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY., Lin P; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY., Higashi RM; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY.; Markey Cancer Center, University of Kentucky, Lexington, KY; and.; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY., Lane AN; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY; twmfan@gmail.com andrew.lane@uky.edu.; Markey Cancer Center, University of Kentucky, Lexington, KY; and.; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2022 Nov 01; Vol. 209 (9), pp. 1674-1690. Date of Electronic Publication: 2022 Sep 23.
DOI:	10.4049/jimmunol.2200178
Abstrakt:	Immunomodulatory (IM) metabolic reprogramming in macrophages (Mϕs) is fundamental to immune function. However, limited information is available for human Mϕs, particularly in response plasticity, which is critical to understanding the variable efficacy of immunotherapies in cancer patients. We carried out an in-depth analysis by combining multiplex stable isotope-resolved metabolomics with reversed phase protein array to map the dynamic changes of the IM metabolic network and key protein regulators in four human donors' Mϕs in response to differential polarization and M1 repolarizer β-glucan (whole glucan particles [WGPs]). These responses were compared with those of WGP-treated ex vivo organotypic tissue cultures (OTCs) of human non-small cell lung cancer. We found consistently enhanced tryptophan catabolism with blocked NAD + and UTP synthesis in M1-type Mϕs (M1-Mϕs), which was associated with immune activation evidenced by increased release of IL-1β/CXCL10/IFN-γ/TNF-α and reduced phagocytosis. In M2a-Mϕs, WGP treatment of M2a-Mϕs robustly increased glucose utilization via the glycolysis/oxidative branch of the pentose phosphate pathway while enhancing UDP- N -acetyl-glucosamine turnover and glutamine-fueled gluconeogenesis, which was accompanied by the release of proinflammatory IL-1β/TNF-α to above M1-Mϕ's levels, anti-inflammatory IL-10 to above M2a-Mϕ's levels, and attenuated phagocytosis. These IM metabolic responses could underlie the opposing effects of WGP, i.e., reverting M2- to M1-type immune functions but also boosting anti-inflammation. Variable reprogrammed Krebs cycle and glutamine-fueled synthesis of UTP in WGP-treated OTCs of human non-small cell lung cancer were observed, reflecting variable M1 repolarization of tumor-associated Mϕs. This was supported by correlation with IL-1β/TNF-α release and compromised tumor status, making patient-derived OTCs unique models for studying variable immunotherapeutic efficacy in cancer patients. (Copyright © 2022 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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