Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells

Oh, Min Hee; Sun, Im-Hong; Zhao, Liang; Leone, Robert D.; Xu, Wei; Collins, Samuel; Tam, Ada; Blosser, Richard L.; Patel, Chirag H.; Englert, Judson M.; Arwood, Matthew L.; Wen, Jiayu; Chan‐Li, Yee; Tenora, Lukáš; Majer, Pavel; Rais, Rana; Slusher, Barbara S.; Horton, Maureen R.; Powell, Jonathan D.

doi:10.1172/jci131859

Cited by 286 publications

(251 citation statements)

References 63 publications

Supporting

Mentioning

245

Contrasting

Order By: Relevance

“…In the context of metabolism, this complex interplay between cancer cells and immune cells present in the micro-environment gives a new dimension to the use of drugs that target metabolic processes (O'Sullivan et al, 2019;Patel et al, 2019). For instance, inhibiting glutamine metabolism has been shown to inhibit tumor growth and increase the sensitivity of triple-negative breast cancers to immune checkpoint blockade (Oh et al, 2020), and reducing oxidative stress has been shown to prevent the generation of tumor-associated macrophages (Zhang et al, 2013). Furthermore, modulating metabolism in T-cells from glycolytic towards an OXPHOS-weighted profile has been shown to improve CAR T cell immunotherapy (Fraietta et al, 2018;O'Sullivan and Pearce, 2015;Sukumar et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Robust metabolic transcriptional components in 34,494 patient-derived samples and cell lines

Leeuwenburgh

Urzúa-Traslaviña

Bhattacharya

et al. 2020

Preprint

View full text Add to dashboard Cite

Patient-derived bulk expression profiles of cancers can provide insight into transcriptional changes that underlie reprogrammed metabolism in cancer. However, these bulk profiles represent the average expression pattern of all heterogeneous tumor and non-tumor cells present in the biopsy. Therefore, subtle transcriptional footprints of metabolic processes can be concealed by other biological processes and experimental artifacts. We therefore performed consensus Independent Component Analyses (c-ICA) with 34,494 bulk expression profiles of patient-derived tumor biopsies, non-cancer tissues and cell lines. c-ICA enabled us to create a transcriptional metabolic landscape in which many robust metabolic transcriptional components (mTCs) and their activation score in individual samples were defined. Here we demonstrate that this metabolic landscape can be used to explore associations between metabolic processes and drug sensitivities, patient outcomes, and the composition of the immune tumor microenvironment. The metabolic landscape can be explored at http://www.themetaboliclandscapeofcancer.com.

show abstract

Section: Discussionmentioning

confidence: 99%

Robust metabolic transcriptional components in 34,494 patient-derived samples and cell lines

Leeuwenburgh

Urzúa-Traslaviña

Bhattacharya

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…In addition to glycolysis, some cells utilize glutamine to maintain mitochondrial metabolites for ATP and macromolecule synthesis 25,26 . Recent work has shown that inhibiting TME glutamine metabolism can impair cancer cell growth while increasing anti-tumor immunity 12,13,15 . In contrast to our finding that glucose uptake is highest in tumor-infiltrating immune cells, we hypothesized that glutamine uptake might more preferentially support cancer cell metabolism.…”

Section: Glutamine Partitions Into Cancer Cellsmentioning

confidence: 99%

“…These data also support the notion that targeting glutamine metabolism presents a specific strategy to hamper cancer cell growth. Intriguingly, this approach also increases glucose consumption by all TME resident cell types and may alter antitumor immunity 12,13,15 . Given the current interest in glutamine-targeting therapeutics, our findings contribute a model of nutrient partitioning that supports their further development.…”

Section: Selective Nutrient Partitioningmentioning

confidence: 99%

“…Recent data from in vivo carbon labeling studies have confirmed that glucose supports anabolic metabolism in transformed cells 10 and in T cells 11 . In addition, glutamine metabolism can support aerobic glycolysis as an anaplerotic or distinct fuel source yet can also restrain glucose-dependent inflammatory differentiation and function of both macrophages and T cells [12][13][14][15] . Glucose uptake in tumor cells is illustrated as a hallmark of malignancy by the prominent role of 18 Ffluorodeoxyglucose positron emission tomography (FDG-PET) imaging in detecting cancers and monitoring therapeutic responses.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Cell Programmed Nutrient Partitioning in the Tumor Microenvironment

Reinfeld

Madden

Wolf

et al. 2020

Preprint

View full text Add to dashboard Cite

The tumor microenvironment (TME) includes transformed cancer and infiltrating immune cells. Cancer cells can consume large quantities of glucose through Warburg metabolism that can be visualized with positron emission tomography (PET). While infiltrating immune cells also rely on glucose, disruptions to metabolism can contribute to tumor immunological evasion. How immune cell metabolism is programmed or restrained by competition with cancer cells for nutrients, remains uncertain. Here we used PET tracers to measure the accessibility of glucose and glutamine to cell subsets in the TME. Surprisingly, myeloid cells including macrophages were the greatest consumers of intra-tumoral glucose, followed by T cells and cancer cells. Cancer cells, in contrast, had the highest glutamine uptake. This distinct nutrient partitioning was programmed through selective mTORC1 signaling and glucose or glutamine-related gene expression. Inhibition of glutamine uptake enhanced glucose uptake across tumor resident cell types and shifted macrophage phenotype, demonstrating glucose is not limiting in the TME. Thus, cancer cells are not the only cells in tumors which exhibit high glucose uptake in vivo and instead preferentially utilize glutamine over other cell types. We observe that intrinsic cellular programs can play a major role in the use of some nutrients. Together, these data argue cell selective partitioning of glucose and glutamine can be exploited to develop therapies and imaging strategies to alter the metabolic programs of specific cell populations in the TME.

show abstract

“…This, in turn, suppresses the development of metastasis and further enhances anti-tumor immunity. Additionally, targeting glutamine metabolism makes it easier for checkpoint blocking drug-resistant tumors to receive immunotherapy [ 62 ]. This proves once again that MDSCs and cancer cells have similar metabolic characteristics to a certain extent, and there is a close interaction between the unique metabolism of tumor and the metabolism of inhibitory immune cells.…”

Section: Metabolism Of Mdscsmentioning

confidence: 99%

Connections between Metabolism and Epigenetic Modification in MDSCs

Dai

Wang

et al. 2020

IJMS

View full text Add to dashboard Cite

Myeloid-derived suppressor cells (MDSCs) are major immunosuppressive cells in the tumor microenvironment (TME). During the differentiation and development of MDSCs from myeloid progenitor cells, their functions are also affected by a series of regulatory factors in the TME, such as metabolic reprogramming, epigenetic modification, and cell signaling pathways. Additionally, there is a crosstalk between these regulatory factors. This review mainly introduces the metabolism (especially glucose metabolism) and significant epigenetic modification of MDSCs in the TME, and briefly introduces the connections between metabolism and epigenetic modification in MDSCs, in order to determine the further impact on the immunosuppressive effect of MDSCs, so as to serve as a more effective target for tumor therapy.

show abstract

Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells

Abstract: Conflict of interest: JDP, BSS, RR, and PM are scientific founders of Dracen Pharmaceuticals and possess equity. Technology arising in part from the studies described herein were patented by Johns Hopkins University and subsequently licensed to Dracen Pharmaceuticals.

Cited by 286 publications

References 63 publications

Robust metabolic transcriptional components in 34,494 patient-derived samples and cell lines

Robust metabolic transcriptional components in 34,494 patient-derived samples and cell lines

Cell Programmed Nutrient Partitioning in the Tumor Microenvironment

Connections between Metabolism and Epigenetic Modification in MDSCs

Contact Info

Product

Resources

About