Metabolism of immune cells in cancer

Leone, Robert D.; Powell, Jonathan D.

doi:10.1038/s41568-020-0273-y

Cited by 535 publications

(472 citation statements)

References 227 publications

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“…Hence, pharmacologic or genetic metabolic reprogramming of either the TME cells or CAR T cells is beginning to accrue. To this end, potential targets have been identified such as IDO, ARG1, CD36, CD39, CD73, GLS, A2AR, AMPK, and PDHK1 [130].…”

Section: Change In the Milieu Of Tmementioning

confidence: 99%

Counteracting CAR T cell dysfunction

et al. 2021

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In spite of high rates of complete remission following chimeric antigen receptor (CAR) T cell therapy, the efficacy of this approach is limited by generation of dysfunctional CAR T cells in vivo, conceivably induced by immunosuppressive tumor microenvironment (TME) and excessive antigen exposure. Exhaustion and senescence are two critical dysfunctional states that impose a pivotal hurdle for successful CAR T cell therapies. Recently, modified CAR T cells with an “exhaustion-resistant” phenotype have shown superior antitumor functions and prolonged lifespan. In addition, several studies have indicated the feasibility of senescence delay in CAR T cells. Here, we review the latest reports regarding blockade of CAR T cell exhaustion and senescence with a particular focus on the exhaustion-inducing pathways. Subsequently, we describe what potential these latest insights offer for boosting the potency of adoptive cell transfer (ACT) therapies involving CAR T cells. Furthermore, we discuss how induction of costimulation, cytokine exposure, and TME modulation can impact on CAR T cell efficacy and persistence, while potential safety issues associated with reinvigorated CAR T cells will also be addressed.

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Section: Change In the Milieu Of Tmementioning

confidence: 99%

Counteracting CAR T cell dysfunction

et al. 2021

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“…Recent work has shown that gastrointestinal tumors exhibit extensive immune in ltration characteristics (31)(32)(33). Therefore, to better understand the role of ITGA5 in GI tumors, the relationship between ITGA5 expression and immune in ltration in GI tumors was investigated using the TIMER database.…”

Section: Relationship Between Itga5 Expression and Immune In Ltrationmentioning

confidence: 99%

ITGA5 Is a Prognostic Biomarker and Correlated with Immune Infiltration In Gastrointestinal Cancers

Zhu

Wang

Zhu

et al. 2020

Preprint

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Background: Integrin Subunit Alpha 5 (ITGA5) belongs to the integrin alpha chain family, is vital for promoting cancer cell invasion, metastasis. However, the correlation between ITGA5 expression and immune infiltration in gastrointestinal (GI) tumors remain unclear.Methods: The expression levels of ITGA5 were detected by Oncomine and Tumor Immune Estimation Resource (TIMER). The association between ITGA5 and prognosis of patients was identified by Kaplan–Meier plotter, Gene Expression Profiling Interactive Analysis 2(GEPIA2) and PrognoScan. We evaluated the correlation between ITGA5 expression and immune infiltrating level via TIMER. Besides, TIMER and immunohistochemistry (IHC) staining were used to explore correlations between ITGA5 expression and markers of immune infiltrates cells. Furthermore, we constructed protein-protein interaction (PPI) network and performed functional enrichment by GeneMANIA and Metascape.Results: ITGA5 was generally overexpressed and correlated with worse prognosis in multiple types of GI tumors. In addition, ITGA5 expression levels was significantly associated with tumor purity and immune infiltration levels of different immune cells in GI tumors. Interestingly, Immune markers for monocytes, tumor - associated macrophages (TAMs), macrophages 2 (M2) cells and T-helper 2 (Th2) cells were found to be significantly and positively correlated with ITGA5 expression levels in colon and gastric cancer. Results from IHC staining further proved that markers of Th2 and M2 cell were significantly increased in gastric cancer patients with high ITGA5 expression levels. Lastly, interaction network and function enrichment analysis revealed ITGA5 were mainly involved in “integrin mediated signaling pathway”, “leukocyte migration”, “cell-substrate adhesion”.Conclutions: our study demonstrated that ITGA5 may act as an essential regulator of tumor immune cell infiltration and a valuable prognostic biomarker in GI tumors. Additional work is needed to fully elucidate the underlying mechanisms behind these observations.

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“…2h). CD4 + Treg mediates the immunosuppression activity in tumor 6 . The pseudotime trajectory analysis was used to characterize the lineage differentiation of TILs.…”

Section: Atpif1 Inactivation Promoted Maturation Of Naïve T Cells Andmentioning

confidence: 99%

“…Metabolic reprogramming is a potential strategy to overcome the energy shortage in T cells by maintaining the energy homeostasis 5 . However, the strategy is limited by a lack of the molecular targets in the metabolic reprogramming 4,6 .…”

Section: Introductionmentioning

confidence: 99%

“…Male and female ATPIF1 -/mice at ages of 6-10 weeks were used in this study with the wild type (WT) littermates in the control. The gender-matched WT mice were used in the control.Tumor growth and tumor-infiltrating T cellsMice were implanted subcutaneously with 1×106 /mouse of B16-F0 melanoma (CRL-6322™, ATCC), Lewis lung cancer (CRL-1642™, ATCC) or B16-OVA melanoma cells (day 0) in the right axilla to establish the tumor-bearing mouse model. Tumor growth was monitored twice/week, and the tumor size was determined by tissue weight after collection from each mouse at about 2 weeks, when the tumor dimension reached about 20 mm in any direction.…”

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confidence: 99%

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ATPIF1 inactivation promotes antitumor immunity through metabolic reprogramming of CD8⁺T cells

Zhong

Wang

Zhang

et al. 2020

Preprint

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Induction of CD8+ T cell activity is a promising strategy in the cancer immunotherapy. In this study, we identified ATP synthase inhibitory factor 1 (ATPIF1) as a potential target in the induction of CD8+ T cell immunity against tumor. Inactivation of ATPIF1 gene in mice promoted the antitumor activity of CD8+ T cells leading to suppression of tumor growth of B16 melanoma and Lewis lung cancer. The phenotype was abolished by deletion of CD8+ T cells in the ATPIF1-KO mice. The tumor infiltrating CD8+ T cells exhibited strong activities in the proliferation, effector and memory as revealed by the single cell RNA sequencing results of CD45+ tumor infiltrating lymphocytes (TILs) isolated from the tumors. The CD8+ T cells expressed more antitumor makers in the tumor microenvironment and in coculture with the tumor cells. The cells had a higher level of glycolysis after the T cell receptor-mediated activation as revealed by the targeted metabolomics assay. The cells exhibited an extra activity of oxidative phosphorylation before the activation as indicated by the oxygen consumption rate. The cells gained capacities in the proliferation, apoptosis resistance and mitophagy in the glucose-limiting environment. These data suggest that inhibition of ATPIF1 activity by gene inactivation rewired the energy metabolism of CD8+ T cells to enhance their immune activities to the tumors. ATPIF1 is a potential molecular target in the induction of antitumor immunity through metabolic reprogramming of CD8+ T cells for the cancer immunotherapy.

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Metabolism of immune cells in cancer

Cited by 535 publications

References 227 publications

Counteracting CAR T cell dysfunction

Counteracting CAR T cell dysfunction

ITGA5 Is a Prognostic Biomarker and Correlated with Immune Infiltration In Gastrointestinal Cancers

ATPIF1 inactivation promotes antitumor immunity through metabolic reprogramming of CD8⁺T cells

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Metabolism of immune cells in cancer

Cited by 535 publications

References 227 publications

Counteracting CAR T cell dysfunction

Counteracting CAR T cell dysfunction

ITGA5 Is a Prognostic Biomarker and Correlated with Immune Infiltration In Gastrointestinal Cancers

ATPIF1 inactivation promotes antitumor immunity through metabolic reprogramming of CD8+T cells

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ATPIF1 inactivation promotes antitumor immunity through metabolic reprogramming of CD8⁺T cells