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Fighting in a wasteland: deleterious metabolites and antitumor immunity
McLane J. Watson, Greg M. Delgoffe
McLane J. Watson, Greg M. Delgoffe
Published January 18, 2022
Citation Information: J Clin Invest. 2022;132(2):e148549. https://doi.org/10.1172/JCI148549.
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Review Series

Fighting in a wasteland: deleterious metabolites and antitumor immunity

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Abstract

As cancers progress, they produce a local environment that acts to redirect, paralyze, exhaust, or otherwise evade immune detection and destruction. The tumor microenvironment (TME) has long been characterized as a metabolic desert, depleted of essential nutrients such as glucose, oxygen, and amino acids, that starves infiltrating immune cells and renders them dysfunctional. While not incorrect, this perspective is only half the picture. The TME is not a metabolic vacuum, only consuming essential nutrients and never producing by-products. Rather, the by-products of depleted nutrients, “toxic” metabolites in the TME such as lactic acid, kynurenine, ROS, and adenosine, play an important role in shaping immune cell function and cannot be overlooked in cancer immunotherapy. Moreover, while the metabolic landscape is distinct, it is not unique, as these toxic metabolites are encountered in non-tumor tissues, where they evolutionarily shape immune cells and their response. In this Review, we discuss how depletion of essential nutrients and production of toxic metabolites shape the immune response within the TME and how toxic metabolites can be targeted to improve current cancer immunotherapies.

Authors

McLane J. Watson, Greg M. Delgoffe

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Figure 1

Depletion of key nutrients and production of toxic by-products impair effector cells but support regulatory cells.

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Depletion of key nutrients and production of toxic by-products impair ef...
Beneficial cells, such as CD8+ and CD4+ effector T (Teff) cells, are depicted at left, and deleterious cells, including Tregs and TAMs, at right. Highly glycolytic tumor cells import glucose via GLUT1 and ferment it to lactate, which is coexported with protons into the TME via MCT1/MCT4. Glucose deprivation impairs the glycolytic capacity of Teff cells, which is key for their proliferation and translation of IFN-γ. Lactic acid impairs Teff cell proliferation by altering the NAD(H) redox balance. Utilization of lactic acid via MCT1 supports Treg proliferation and suppressive function. Lactic acid contributes to histone lactylation, which supports the expression of M2-like genes such as Arg1 in macrophages. Tryptophan is depleted via IDO expressed by MDSCs, TAMs, and tumor cells. Tryptophan depletion triggers the stress response kinase GCN2 and suppresses the mTOR pathway, reducing proliferation, altering memory differentiation, reducing activation of Teff cells, and inducing a regulatory phenotype in naive T cells. Kynurenine, imported via SLC7A5/8, engages with the AhR to increase PD-1 and Foxp3 expression. Kynurenine-induced ROS inhibit IL-2 signaling critical for T cell survival. Depletion of oxygen in the TME inhibits oxidative metabolism and decreases the mitochondrial mass of CD8+ T cells. ROS both intra- and extracellularly drive partnerless nuclear factor of activated T cells (NFAT) signaling and expression of PD-1 and Tim-3 in CD8+ T cells while promoting NFAT/Foxp3 signaling in Tregs. Oxygen depletion promotes extracellular accumulation of ATP, which is broken down to adenosine by the cell-surface ectonucleotidases CD39 and CD73. Adenosine acts through A2AR to impair IL-2 and IFN-γ production and increase PD-1 expression in Teff cells, while activating Foxp3 and CTLA4 expression to promote the development of Tregs.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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