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Getting Started in Immunometabolism – Literature Resources for Progenitors and Tumor Immunity

Immune cells use the well-known metabolic pathways of oxidative phosphorylation, glycolysis, and fatty acid oxidation to different extents to accomplish different immune functions. Many, many factors affect metabolic state of any particular cell. These include cell-specific factors like cell type and cell state (activation, differentiation, proliferation, migration). They also include site-specific factors such as tissue site and state (normal, disease, injury, infection). Any cell’s metabolic state can be affected by the relative availability of nutrients and oxygen. However, the immune cell microenvironment provides a new context in which to connect specific functions in immunity with physiologic conditions such as blood delivery and competition for oxygen by nearby cells or microbes. Most importantly, these new connections give us a better picture of physiologically relevant in vitro assay conditions for translatability and reproducibility.

A Few Recent Reviews on Metabolism as Immunomodulator [1] [2] [3] [4]


Hematopoietic Stem Cell Metabolism and Microenvironment

• The physiology of the blood, nutrient, and oxygen delivery in the bone marrow hematopoietic stem cell niche favors very low oxygen levels (Reviewed in [5]) [6]

• HSC yields from cord blood or marrow are higher when isolated in physioxia [7]

• Elevated intracellular ROS levels reduce engraftment [8]


Pathologic Hypoxia and Inflammation (reviewed in [9])

• High altitude exposure can result in inflammation of tissues [9]

• Wounds and sites of inflammation are hypoxic [10] [11] [12] [13] [14]

• Ischemia/reperfusion (embolism or grafts) is followed by inflammation [15]


The Tumor Microenvironment

• Tumor infiltrating lymphocytes (TIL) compete with highly glycolytic tumor cells for glucose and oxygen in poorly vascularized tumors (reviewed in [16])

• Lung may be immunologically permissive for metastasis due to higher O2 [17]

• CAR-T that express the CAR protein only upon HIF-1a induction, may increase anti-tumor cytotoxicity and specificity in solid tumors [18] Controlled In Vitro O2 is Critical for Translatability and Reproducibility in Immunology

• Even lung cell cultures experience oxygen artifact cultured in room air [19]

• Hypoxic Pre-conditioning in vitro may improve immune cell function in vivo [20]

• Isolation of HSC in room air O2 cuts yields and engraftment [7]

• The proper oxygen level in vitro is critical for physiologically relevant findings in lymphocyte assays [21] [22]




1. Loftus, R.M. and D.K. Finlay, Immunometabolism: Cellular Metabolism Turns Immune Regulator. J Biol Chem, 2016. 291(1): p. 1-10.

2. MacIver, N.J., R.D. Michalek, and J.C. Rathmell, Metabolic regulation of T lymphocytes. Annu Rev Immunol, 2013. 31: p. 259-83.

3. Zeng, H. and H. Chi, mTOR and lymphocyte metabolism. Curr Opin Immunol, 2013. 25(3): p. 347-55.

4. Murray, P.J., J. Rathmell, and E. Pearce, SnapShot: Immunometabolism. Cell Metab, 2015. 22(1): p. 190-190 e1.

5. Morrison, S.J. and D.T. Scadden, The bone marrow niche for haematopoietic stem cells. Nature, 2014. 505(7483): p. 327-34.

6. Itkin, T., et al., Distinct bone marrow blood vessels differentially regulate haematopoiesis. Nature, 2016. 532(7599): p. 323-328.

7. Mantel, C.R., et al., Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock. Cell, 2015. 161(7): p. 1553-65.

8. Ronn, R.E., et al., Reactive Oxygen Species Impair the Function of CD90+ Hematopoietic Progenitors Generated from Human Pluripotent Stem Cells. Stem Cells, 2017. 35(1): p. 197-206.

9. Eltzschig, H.K. and P. Carmeliet, Hypoxia and inflammation. N Engl J Med, 2011. 364(7): p. 656-65.

10. Goggins, B.J., et al., Hypoxia Inducible Factor (HIF)-1 accelerates epithelial wound healing through integrin regulation. The FASEB Journal, 2017. 31(1 Supplement): p. 465.11.

11. Fuchs, K., et al., In Vivo Hypoxia PET Imaging Quantifies the Severity of Arthritic Joint Inflammation in Line with Overexpression of Hypoxia-Inducible Factor and Enhanced Reactive Oxygen Species Generation. Journal of Nuclear Medicine, 2017. 58(5): p. 853-860.

12. Colgan, S.P., E.L. Campbell, and D.J. Kominsky, Hypoxia and Mucosal Inflammation. Annu Rev Pathol, 2016. 11: p. 77-100.

13. Garcia-Contreras, M., et al., A Metabolomics Study of the Effects of Inflammation, Hypoxia, and High Glucose on Isolated Human Pancreatic Islets. J Proteome Res, 2017.

14. Semenza, G.L., Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol, 2014. 9: p. 47-71.

15. Quaegebeur, A., et al., Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism. Cell Metab, 2016. 23(2): p. 280-91.

16. Zhang, Y. and H.C. Ertl, Starved and Asphyxiated: How Can CD8 T Cells within a Tumor Microenvironment Prevent Tumor Progression. Front Immunol, 2016. 7: p. 32.

17. Clever, D., et al., Oxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche. Cell, 2016. 166(5): p. 1117-1131.e14.

18. Juillerat, A., et al., An oxygen sensitive self-decision making engineered CAR T-cell. Sci Rep, 2017. 7: p. 39833.

19. Kumar, A., et al., Quantifying the magnitude of the oxygen artefact inherent in culturing airway cells under atmospheric oxygen versus physiological levels. FEBS Lett, 2016. 590(2): p. 258-69.

20. Colmone, A., Hypoxic conditioning of immune cells. Science, 2017. 355(6326): p. 706.

21. Vuillefroy de Silly, R., et al., Phenotypic switch of CD8+ T cells reactivated under hypoxia toward IL‐10 secreting, poorly proliferative effector cells. European journal of immunology, 2015.

22. Zenewicz, L.A., Oxygen Levels and Immunological Studies. Frontiers in Immunology, 2017. 8(324).