Editors' ChoiceCancer

Glutamine: A bad guy for antitumor immunity?

See allHide authors and affiliations

Science Translational Medicine  06 May 2020:
Vol. 12, Issue 542, eabb7093
DOI: 10.1126/scitranslmed.abb7093


Glutamine antagonism enhances antitumor immunity by reprogramming myeloid cells.

Glutamine, the most abundant circulating amino acid in our body, is an essential nutrient for tumor growth, a phenomenon known as “glutamine addiction.” Numerous early clinical trials targeted glutamine metabolism for cancer therapy but were eventually terminated because of life-threatening toxicity, particularly to the gut. In addition, recent immunometabolism studies showed that glutamine is required for activation and function of immune cells that are critical for driving protective antitumor immunity, posing a metabolic conundrum. Thus, identifying effective strategies to overcome these obstacles could provide a substantial leap forward in treating cancer.

In a recent study, Oh et al. used JHU083, a prodrug that broadly inhibits glutamine-metabolizing enzymes and is selectively activated in the tumor microenvironment (TME). Their results showed that JHU083 not only potently suppressed primary tumor growth and metastasis but, more interestingly, also caused a drastic reduction of immunosuppressive myeloid-derived suppressor cells (MDSCs). Mechanistically, JHU083 induced apoptosis of MDSCs, blocked trafficking of MDSCs to the tumor bed, and converted MDSCs to proinflammatory and antitumor M1 macrophages. Although the total number of tumor-associated macrophages (TAMs) remained unchanged, JHU083 reprogrammed TAMs to M1 macrophages, which were activated by induced immunogenic tumor cell death and released danger-associated molecular patterns. Functionally, these M1-like TAMs cross-presented tumor antigens to CD8+ T cells, resulting in enhanced activation, proliferation, and effector functions of the CD8+ T cells. Given these immunostimulatory effects of JHU083, the authors tested the combination therapy of JHU083 and immune checkpoint inhibitors (ICIs) and observed additive therapeutic effects without overt toxicity, even in tumors that are resistant to ICIs. Collectively, blockade of glutamine metabolism suppressed tumor growth and metastasis by reprogramming myeloid cells and metabolically reshaping the TME.

These results—together with a previous finding that JHU083 directly activated CD8+ T cells—challenge the concept that glutamine is needed for immune cells’ activation and function. Future work needs to be done to determine whether this is related to specific features of the TME. Despite these intriguing preclinical results, caution should be taken given the long history of failures targeting glutamine metabolism, and clinical testing of the toxicity, tolerability, and clinical efficacy of JHU083 will be key. Nevertheless, this is an exciting start.

Highlighted Article

View Abstract

Stay Connected to Science Translational Medicine

Navigate This Article