Fundamentals of T Cell Metabolism and Strategies to Enhance Cancer Immunotherapy

Rivera, Guillermo O. Rangel; Knochelmann, Hannah M.; Dwyer, Connor J.; Smith, Aubrey S.; Wyatt, Megan; Rivera-Reyes, Amalia M; Thaxton, Jessica E.; Paulos, Chrystal M.

doi:10.3389/fimmu.2021.645242

Cited by 80 publications

(62 citation statements)

References 179 publications

(263 reference statements)

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“…Tumor metabolism involves glucose metabolism, amino acid metabolism, lipid metabolism, and many other phenomena. Inhibition of cancer cell metabolism is a current tumor treatment goal [36]. In the liver, the synthesis of non-essential amino acids plays an important role in maintaining function.…”

Section: Discussionmentioning

confidence: 99%

Cepharanthine inhibits hepatocellular carcinoma cell growth and proliferation by regulating amino acid metabolism and suppresses tumorigenesis in vivo

Feng¹,

Pan²,

Wu³

et al. 2021

Int. J. Biol. Sci.

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Cepharanthine (CEP), a natural compound extracted from Stephania cepharantha Hayata, has been found to have the potential to treat a variety of tumors in recent years. This study aims to evaluate the anti-hepatocellular carcinoma (HCC) effect of CEP and determine its in-depth mechanism. In this study, Hep3B and HCCLM3 cells were selected to evaluate the antitumor effects of CEP in vitro, whereas tumor xenograft in nude mice was performed to make in vivo anti-tumor assessment. RNA-sequence (RNA-seq) was used to identify possible molecular targets and pathways. Further, gas chromatography mass spectrometry (GC-MS) was performed to assess the differential metabolites involved in mediating the effect of CEP on the HCC cell line. Our results showed that CEP treatment resulted in the dose-dependent inhibition of cell viability, migration, and proliferation and could also induce apoptosis in HCC cells. RNA-seq following CEP treatment identified 168 differentially expressed genes (DEGs), which were highly enriched in metabolism-associated pathways. In addition, CEP down-regulated many metabolites through the amino acid metabolism pathway. In vivo experiment showed that CEP significantly suppressed tumor growth. Our results indicate that CEP has significant antitumor effects and has the potential to be a candidate drug for HCC treatment.

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Section: Discussionmentioning

confidence: 99%

Cepharanthine inhibits hepatocellular carcinoma cell growth and proliferation by regulating amino acid metabolism and suppresses tumorigenesis in vivo

Feng¹,

Pan²,

Wu³

et al. 2021

Int. J. Biol. Sci.

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“… 46 The glycolysis is enhanced in activated T cells and the oxidative phosphorylation is predominantly used in naive and memory T cells. 47 PI3K signaling activated by TCR stimulation triggers the recruitment of Glut1 from the cytoplasmic pool to cell surface. Increased Glut1 expression and glucose uptake by activated T cells is accompanied with increased glycolysis.…”

Section: Discussionmentioning

confidence: 99%

Cancer immunotherapy with PI3K and PD-1 dual-blockade via optimal modulation of T cell activation signal

Isoyama

Mori

Sugiyama

et al. 2021

J Immunother Cancer

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BackgroundImmune checkpoint blockade (ICB) induces durable clinical responses in patients with various types of cancer. However, its limited clinical efficacy requires the development of better approaches. In addition to immune checkpoint molecules, tumor-infiltrating immunosuppressive cells including regulatory T cells (Tregs) play crucial roles in the immune suppressive tumor microenvironment. While phosphatidylinositol 3-kinase (PI3K) inhibition as a Treg-targeted treatment has been implicated in animal models, its effects on human Tregs and on the potential impairment of effector T cells are required to be clarified for successful cancer immunotherapy.MethodsThe impact of a selective-PI3K inhibitor ZSTK474 with or without anti-programmed cell death 1 (PD-1) monoclonal antibody on Tregs and CD8+ T cells were examined with in vivo animal models and in vitro experiments with antigen specific and non-specific fashions using peripheral blood from healthy individuals and cancer patients. Phenotypes and functions of Tregs and effector T cells were examined with comprehensive gene and protein expression assays.ResultsImproved antitumor effects by the PI3K inhibitor in combination with ICB, particularly PD-1 blockade, were observed in mice and humans. Although administration of the PI3K inhibitor at higher doses impaired activation of CD8+ T cells as well as Tregs, the optimization (doses and timing) of this combination treatment selectively decreased intratumoral Tregs, resulting in increased tumor antigen-specific CD8+ T cells in the treated mice. Moreover, on the administration of the PI3K inhibitor with the optimal dose for selectively deleting Tregs, PI3K signaling was inhibited not only in Tregs but also in activated CD8+ T cells, leading to the enhanced generation of tumor antigen-specific memory CD8+ T cells which contributed to durable antitumor immunity. These opposing outcomes between Tregs and CD8+ T cells were attributed to the high degree of dependence on T cell signaling in the former but not in the latter.ConclusionsPI3K inhibitor in the combination with ICB with the optimized protocol fine-tuned T cell activation signaling for antitumor immunity via decreasing Tregs and optimizing memory CD8+ T cell responses, illustrating a promising combination therapy.

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“…The enrichment analysis of genes in this module also reveals the activation of T cells (Figure 3D). We believed that T cell immunity in low-grade malignancy might help avoid metastasis (12). The yellow module is unique in CS II.…”

Section: The Unique Gene Expression Modules In Cs I and Cs Iimentioning

confidence: 99%

The Key Gene Expression Patterns and Prognostic Factors in Malignant Transformation from Enchondroma to Chondrosarcoma

Wu¹,

Huang²,

Yu³

et al. 2021

Front. Oncol.

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Enchondroma (EC) is a common benign bone tumor. It has the risk of malignant transformation to Chondrosarcoma (CS). However, the underlying mechanism is unclear. The gene expression profile of EC and CS was obtained from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified using GEO2R. We conducted the enrichment analysis and constructed the gene interaction network using the DEGs. We found that the epithelial-mesenchymal transition (EMT) and the VEGFA-VEGF2R signaling pathway were more active in CS. The CD8+ T cell immunity was enhanced in CS I. We believed that four genes (MFAP2, GOLM1, STMN1, and HN1) were poor predictors of prognosis, while two genes (CAB39L and GAB2) indicated a good prognosis. We have revealed the mechanism in the tumor progression and identified the key genes that predicted the prognosis. This study provided new ideas for the diagnosis and treatment of EC and CS.

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Fundamentals of T Cell Metabolism and Strategies to Enhance Cancer Immunotherapy

Cited by 80 publications

References 179 publications

Cepharanthine inhibits hepatocellular carcinoma cell growth and proliferation by regulating amino acid metabolism and suppresses tumorigenesis in vivo

Cepharanthine inhibits hepatocellular carcinoma cell growth and proliferation by regulating amino acid metabolism and suppresses tumorigenesis in vivo

Cancer immunotherapy with PI3K and PD-1 dual-blockade via optimal modulation of T cell activation signal

The Key Gene Expression Patterns and Prognostic Factors in Malignant Transformation from Enchondroma to Chondrosarcoma

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