Immunomodulatory (IM) metabolic reprogramming in macrophages (Mfs) is fundamental to immune function. However, limited information is available for human Mfs, 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’ Mfs in response to differential polarization and M1 repolarizer b-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 Mfs (M1-Mfs), which was associated with immune activation evidenced by increased release of IL-1b/CXCL10/IFN-γ/TNF-a and reduced phagocytosis. In M2a-Mfs, WGP treatment of M2a-Mfs 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-1b/TNF-a to above M1-Mf’s levels, anti-inflammatory IL-10 to above M2a-Mf’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 Mfs. This was supported by correlation with IL-1b/TNF-a release and compromised tumor status, making patient-derived OTCs unique models for studying variable immunotherapeutic efficacy in cancer patients.
|Number of pages||17|
|Journal||Journal of Immunology|
|State||Published - Nov 1 2022|
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health (NIH), National Cancer Institute Grants P01CA163223-01A1 and 1U24DK097215-01A1; NIH, National Institute of Diabetes and Digestive and Kidney Diseases Grant 1R01CA118434-01A2; NIH, National Institute of Environmental Health Sciences Grants 5R21ES025669-02 and 5R01ES22191; NIH, National Institute of General Medical Sciences Grant 5P20GM121327; shared resource(s) of the University of Kentucky Markey Cancer Center Grant P30CA177558; and endowment funds to T.W.-M.F. and A.N.L.
Copyright © 2022 by The American Association of Immunologists, Inc.
ASJC Scopus subject areas
- Immunology and Allergy