Uncoupling protein 2 reprograms the tumor microenvironment to support the anti-tumor immune cycle

Cheng, Wan-Chen; Tsui, Yao‐Chen; Ragusa, Simone; Koelzer, Viktor H.; Mina, Marco; Franco, Fabien; Läubli, Heinz; Tschumi, Benjamin; Speiser, Daniel E.; Romero, Pedro; Zippelius, Alfred; Petrova, Tatiana V.; Mertz, Kirsten D.; Ciriello, Giovanni; Ho, Ping‐Chih

doi:10.1038/s41590-018-0290-0

Cited by 56 publications

(56 citation statements)

References 53 publications

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“…27 29 30 Consistently, CD8 + T cells were decreased in the TMEs and DLNs of Hdac9 -/mice in this study. Recently, Cheng et al 31 proposed that expressing mitochondrial uncoupling protein 2 in tumor cells could disrupt the immunosuppressive state of the TME by boosting cDC1-and CD8 + T cell-dependent antitumor immunity. By contrast, Yan et al 32 reported that in the central nervous system, the presence of fibrinogen-like protein 2 in tumor cells inhibited granulocyte-macrophage colony-stimulating factor-induced CD103 + DC differentiation and promoted tumor progression.…”

Section: Discussionmentioning

confidence: 99%

HDAC9 deficiency promotes tumor progression by decreasing the CD8⁺dendritic cell infiltration of the tumor microenvironment

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et al. 2020

J Immunother Cancer

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BackgroundThe tumor microenvironment (TME) contains a variety of immune cells, which play critical roles during the multistep development of tumors. Histone deacetylase 9 (HDAC9) has been reported to have either proinflammatory or anti-inflammatory effects, depending on the immune environment. In this study, we investigated whether HDAC9 in the tumor stroma regulated inflammation and antitumor immunity.MethodsHdac9 knockout mice were generated to analyze the HDAC9-associated inflammation and tumor progression. Immune cells and cytokines in TME or draining lymph nodes were quantified by flow cytometry and quantitative reverse transcription-PCR. The antigen presentation and CD8+ T cell priming by tumor-infiltrating dendritic cells (DCs) were evaluated in vitro and in vivo. HDAC9-associated inflammation was investigated in a mouse model with dextran sulfate sodium–induced colitis. Correlation of HDAC9 with CD8+ expression was assessed in tissue sections from patients with non-small cell lung cancer.ResultsHDAC9 deficiency promoted tumor progression by decreasing the CD8+ DC infiltration of the TME. Compared with wild-type mice, the tumor-infiltrating DCs of Hdac9-/- mice displayed impaired cross-presentation of tumor antigens and cross-priming of CD8+ T cells. Moreover, HDAC9 expression was significantly positively correlated with CD8+ cell counts in human lung cancer stroma samples.ConclusionsHDAC9 deficiency decreased inflammation and promoted tumor progression by decreasing CD8+ DC infiltration of the TME. HDAC9 expression in the tumor stroma may represent a promising biomarker to predict the therapeutic responses of patients receiving CD8+ T cell-dependent immune treatment regimens.

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Section: Discussionmentioning

confidence: 99%

HDAC9 deficiency promotes tumor progression by decreasing the CD8⁺dendritic cell infiltration of the tumor microenvironment

Ning

Ding

Sun

et al. 2020

J Immunother Cancer

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“…Filtered cells were incubated with ACK lysis buffer (Invitrogen) to lyse red blood cells and then washed with fluorescent activated cell sorter (FACS) buffer (phosphate-buffered saline with 2% fetal bovine serum and 2 mM EDTA). Tumor-infiltrating leukocytes were further enriched by percoll density gradient centrifugation (800x g , 30 min) at room temperature as described before 51 .…”

Section: Methodsmentioning

confidence: 99%

CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors

et al. 2020

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Depleting regulatory T cells (T reg cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral T reg cells is direly needed for cancer immunotherapy. We found CD36 was selectively up-regulated in intrautumoral T reg cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via PPAR-β signaling, programming T reg cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in T reg cells suppressed tumor growth accompanied by a decrease in intratumoral T reg cells and enhancement of anti-tumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive anti-tumor responses with anti-PD-1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrate survival and functions of intratumoral T reg cells, and the therapeutic potential of targeting this pathway for reprogramming the TME.

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“…Recent publications also underline the reprogrammation of the immunosuppressive TME through metabolic alterations of tumor cells. The best example is the overexpression of the C4-metabolite carrier UCP2 in melanoma cells triggering the engagement of anti-tumor immune responses following CXCL10 secretion in the TME (172). Thus, tumor metabolism modulates tumor immune evasion through nutrients availability for T cells and reprogrammation of the TME.…”

Section: Metabolic Targeting Of Gscsmentioning

confidence: 99%

Glioblastoma Stem-Like Cells, Metabolic Strategy to Kill a Challenging Target

et al. 2019

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Over the years, substantial evidence has definitively confirmed the existence of cancer stem-like cells within tumors such as Glioblastoma (GBM). The importance of Glioblastoma stem-like cells (GSCs) in tumor progression and relapse clearly highlights that cancer eradication requires killing of GSCs that are intrinsically resistant to conventional therapies as well as eradication of the non-GSCs cells since GSCs emergence relies on a dynamic process. The past decade of research highlights that metabolism is a significant player in tumor progression and actually might orchestrate it. The growing interest in cancer metabolism reprogrammation can lead to innovative approaches exploiting metabolic vulnerabilities of cancer cells. These approaches are challenging since they require overcoming the compensatory and adaptive responses of GSCs. In this review, we will summarize the current knowledge on GSCs with a particular focus on their metabolic complexity. We will also discuss potential approaches targeting GSCs metabolism to potentially improve clinical care.

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Uncoupling protein 2 reprograms the tumor microenvironment to support the anti-tumor immune cycle

Cited by 56 publications

References 53 publications

HDAC9 deficiency promotes tumor progression by decreasing the CD8⁺dendritic cell infiltration of the tumor microenvironment

HDAC9 deficiency promotes tumor progression by decreasing the CD8⁺dendritic cell infiltration of the tumor microenvironment

CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors

Glioblastoma Stem-Like Cells, Metabolic Strategy to Kill a Challenging Target

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Uncoupling protein 2 reprograms the tumor microenvironment to support the anti-tumor immune cycle

Cited by 56 publications

References 53 publications

HDAC9 deficiency promotes tumor progression by decreasing the CD8+dendritic cell infiltration of the tumor microenvironment

HDAC9 deficiency promotes tumor progression by decreasing the CD8+dendritic cell infiltration of the tumor microenvironment

CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors

Glioblastoma Stem-Like Cells, Metabolic Strategy to Kill a Challenging Target

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Product

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HDAC9 deficiency promotes tumor progression by decreasing the CD8⁺dendritic cell infiltration of the tumor microenvironment

HDAC9 deficiency promotes tumor progression by decreasing the CD8⁺dendritic cell infiltration of the tumor microenvironment