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Metabolic remodeling contributes towards an immune-suppressive phenotype in glioblastoma

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Abstract

Glioblastoma (GBM) is one of the most aggressive tumors. Numerous studies in the field of immunotherapy have focused their efforts on identifying various pathways linked with tumor-induced immunosuppression. Recent research has demonstrated that metabolic reprogramming in a tumor can contribute towards immune tolerance. To begin to understand the interface between metabolic remodeling and the immune-suppressive state in GBM, we performed a focused, integrative analysis coupling metabolomics with gene-expression profiling in patient-derived GBM (n = 80) and compared them to low-grade astrocytoma (LGA; n = 28). Metabolic intermediates of tryptophan, arginine, prostaglandin, and adenosine emerged as immuno-metabolic nodes in GBM specific to the mesenchymal and classical molecular subtypes of GBM. Integrative analyses emphasized the importance of downstream metabolism of several of these metabolic pathways in GBM. Using CIBERSORT to analyze immune components from the transcriptional profiles of individual tumors, we demonstrated that tryptophan and adenosine metabolism resulted in an accumulation of Tregs and M2 macrophages, respectively, and was recapitulated in mouse models. Furthermore, we extended these findings to preclinical models to determine their potential utility in defining the biologic and/or immunologic consequences of the identified metabolic programs. Collectively, through integrative analysis, we uncovered multifaceted ways by which metabolic reprogramming may contribute towards immune tolerance in GBM, providing the framework for further investigations designed to determine the specific immunologic consequence of these metabolic programs and their therapeutic potential.

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Abbreviations

1-L-MT:

1-Methyl-l-tryptophan

AD-H:

Adenosine pathway metabolites-high

AD-L:

Adenosine pathway metabolites-low

AHR:

Aryl hydrocarbon receptor

ARG-H:

Arginine pathway metabolites-high

ARG-L:

Arginine pathway metabolites-low

ARG2:

Arginase 2

ASL:

Argininosuccinate lyase

CBR:

Carbonyl reductase

CIBERSORT:

Cell-type identification by estimating relative subsets of RNA transcripts

CKMT1:

Creatine kinase, mitochondrial 1A

COX:

Cyclooxygenase

GBM:

Glioblastoma

GSCs:

Glioma stem cells

IDH1:

Isocitrate dehydrogenase 1

IL2-Rα:

Interleukin 2 receptor-subunit alpha

KEGG:

Kyoto encyclopedia of genes and genomes

KMO:

3-Mono-oxygenase

KYAT:

Kynurenine aminotransferase

KYNU:

Kynureninase

LGA:

Low-grade astrocytoma

MGMT:

O6-methylguanine–DNA methyltransferase

MSP:

Methylation-specific PCR

NAD:

Nicotinamide adenine dinucleotide

NOS1:

Nitric oxide synthase 1

PG-H:

Prostaglandin pathway metabolites-high

PG-L:

Prostaglandin pathway metabolites-low

PGE2:

Prostaglandin E2

PGF2A:

Prostaglandin F2 alpha

PGG2:

Prostaglandin G2

PGH2:

Prostaglandin H2

PLS:

Partial least squares

PTGES:

Prostaglandin E synthase

PTGIS:

Prostaglandin I synthase

PTGS:

Prostaglandin-endoperoxide synthase

QPRT:

Quinolinate phosphoribosyltransferase

TCGA:

The cancer genome atlas

TDO:

Tryptophan 2,3-dioxygenase

TRP-H:

Tryptophan pathway metaboliteshigh

TRP-L:

Tryptophan pathway metaboliteslow

VIP:

Variable importance in projection

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Funding

This work was supported by the National Institute of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) (R21NS090087), American Cancer Society (RSG-11-029-01), Bankhead-Coley Cancer Research Program and Cancer Research Seed Grant Awards from Beaumont Health to Prakash Chinnaiyan.

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Authors and Affiliations

  1. Department of Radiation Oncology, Beaumont Health, 3811 West Thirteen Mile Road, Royal Oak, MI, 48073, USA

    Pravin Kesarwani, Antony Prabhu, Shiva Kant & Prakash Chinnaiyan

  2. Oakland University William Beaumont School of Medicine, Royal Oak, MI, USA

    Prakash Chinnaiyan

Authors
  1. Pravin Kesarwani
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  2. Antony Prabhu
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  3. Shiva Kant
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  4. Prakash Chinnaiyan
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Contributions

Study design: PK and PC; experiments: PK, AP, and SK; data analysis: PK and PC; reagents: PC; and manuscript preparation: PK and PC.

Corresponding author

Correspondence to Prakash Chinnaiyan.

Ethics declarations

Conflict of interest

The authors declare that they have no potential conflict of interest.

Ethical approval

GBM/glioma tissue samples were obtained from the Moffitt Cancer Center Tissue Core Facility. Institutional Review Board/Human Subjects approval (MCC16197) was obtained for this retrospective study from the ethics committee of the Moffitt Cancer Center. All animal studies were carried out under protocols approved by the IACUC (AL-16-09 and AL-18-10) at William Beaumont Research Institute.

Informed consent

Patients gave written informed consent for the use of their specimens and clinical data for research and publication prior to surgical resection or following diagnosis under the Total Cancer Care Tissue Repository program at the Moffitt Cancer Center.

Animal source

C57BL/6 (H-2b, CD45.2) and athymic nu/nu (NU-Foxn1nu) mice were purchased from Charles River Laboratories (Wilmington, MA).

Cell line authentication

Human GBM cell lines U87, U251, and T98G were purchased from ATCC and authenticated by STR analysis at The University of Arizona Genetics Core. MES83, MES326, PN19, and PN84 were generated, obtained, and authenticated by Dr. Ichiro Nakano’s lab at Ohio State University. Murine TRP cell lines were generated, obtained, and authenticated by Dr. C. Ryan Miller’s lab at The University of North Carolina School of Medicine.

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Kesarwani, P., Prabhu, A., Kant, S. et al. Metabolic remodeling contributes towards an immune-suppressive phenotype in glioblastoma. Cancer Immunol Immunother 68, 1107–1120 (2019). https://doi.org/10.1007/s00262-019-02347-3

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  • DOI: https://doi.org/10.1007/s00262-019-02347-3

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