Enhanced glutamine uptake influences composition of immune cell infiltrates in breast cancer

Ansari, Rokaya El; Craze, Madeleine L.; Althobiti, Maryam; Alfarsi, Lutfi; Ellis, Ian O.; Rakha, Emad A.; Green, Andrew

doi:10.1038/s41416-019-0626-z

Cited by 41 publications

(42 citation statements)

References 59 publications

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“…Lack of glutamine and glucose in the TME may shift ratios of T cell subsets by supporting the development of regulatory T cells (Treg) rather than effector T cells such as T helper 1 (Th1) cells and Th17 cells ( 1 , 27 , 28 ). For example, the overexpression of SLC1A5, SLC3A2, and SLC7A5 in breast cancer is significantly associated with the existence of Foxp3+ Tregs and poor patient survival ( 29 ). Treg cells and other infiltrating regulatory cells, such as highly anabolic tolerogenic dendritic cells, also compete for the nutrients and contribute to the nutrient-limited TME.…”

Section: The Tumor Microenvironment: a Battlefield With Limited Nutrientsmentioning

confidence: 99%

Targeting SLC1A5 and SLC3A2/SLC7A5 as a Potential Strategy to Strengthen Anti-Tumor Immunity in the Tumor Microenvironment

et al. 2021

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Cancer cells are metabolically vigorous and are superior in the uptake of nutrients and in the release of the tumor microenvironment (TME)-specific metabolites. They create an acidic, hypoxic, and nutrient-depleted TME that makes it difficult for the cytotoxic immune cells to adapt to the metabolically hostile environment. Since a robust metabolism in immune cells is required for optimal anti-tumor effector functions, the challenges caused by the TME result in severe defects in the invasion and destruction of the established tumors. There have been many recent developments in NK and T cell-mediated immunotherapy, such as engineering them to express chimeric antigen receptors (CARs) to enhance tumor-recognition and infiltration. However, to defeat the tumor and overcome the limitations of the TME, it is essential to fortify these novel therapies by improving the metabolism of the immune cells. One potential strategy to enhance the metabolic fitness of immune cells is to upregulate the expression of nutrient transporters, specifically glucose and amino acid transporters. In particular, the amino acid transporters SLC1A5 and SLC7A5 as well as the ancillary subunit SLC3A2, which are required for efficient uptake of glutamine and leucine respectively, could strengthen the metabolic capabilities and effector functions of tumor-directed CAR-NK and T cells. In addition to enabling the influx and efflux of essential amino acids through the plasma membrane and within subcellular compartments such as the lysosome and the mitochondria, accumulating evidence has demonstrated that the amino acid transporters participate in sensing amino acid levels and thereby activate mTORC1, a master metabolic regulator that promotes cell metabolism, and induce the expression of c-Myc, a transcription factor essential for cell growth and proliferation. In this review, we discuss the regulatory pathways of these amino acid transporters and how we can take advantage of these processes to strengthen immunotherapy against cancer.

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Section: The Tumor Microenvironment: a Battlefield With Limited Nutrientsmentioning

confidence: 99%

Targeting SLC1A5 and SLC3A2/SLC7A5 as a Potential Strategy to Strengthen Anti-Tumor Immunity in the Tumor Microenvironment

et al. 2021

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“…Cancer metabolism affects the whole TME and drives the insurgence of drug resistance, jeopardizing immunotherapy efficiency [ 113 ]. El Ansari and colleagues [ 114 ] developed an siRNA-based strategy targeting SLC7A5, which mediates the efflux of glutamine and the influx of leucine and is upregulated in breast cancer [ 115 ]. Interestingly, siRNA-mediated SLC7A5 knockdown resulted in a decrease in PD-L1 expression level within the tumor.…”

Section: Sirna Therapeutics Targeting the Tmementioning

confidence: 99%

Modulating the Crosstalk between the Tumor and the Microenvironment Using SiRNA: A Flexible Strategy for Breast Cancer Treatment

Roscigno

Scognamiglio

Ingenito

et al. 2020

Cancers

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Tumorigenesis is a complex and multistep process in which sequential mutations in oncogenes and tumor-suppressor genes result in enhanced proliferation and apoptosis escape. Over the past decades, several studies have provided evidence that tumors are more than merely a mass of malignant cancer cells, with the tumor microenvironment (TME) also contributing to cancer progression. For this reason, the focus of cancer research in recent years has shifted from the malignant cancer cell itself to the TME and its interactions. Since the TME actively participates in tumor progression, therapeutic strategies targeting it have created great interest. In this context, much attention has been paid to the potential application of small interfering RNA (siRNA), a class of non-coding RNA that has the ability to downregulate the expression of target genes in a sequence-specific way. This is paving the way for a novel therapeutic approach for the treatment of several diseases, including cancer. In this review, we describe recent efforts in developing siRNA therapeutics for the treatment of breast cancer, with particular emphasis on TME regulation. We focus on studies that adapt siRNA design to reprogram/re-educate the TME and eradicate the interplay between cancer cells and TME.

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“…Previous studies have shown that CD4 + T cells and tumor-associated macrophages (TAMs) play a central role in pro-tumor immunity; their interactions with tumor cells can directly promote tumor growth, progression, invasion, and metastasis. Conversely, CD8 + T cells are responsible for antitumor responses, and increased CD8 + T cell infiltration usually indicates a better prognosis in LIHC (Yan et al, 2018;Ansari et al, 2020;Li et al, 2020). In summary, these data indicate that PDZD11 is not only a prognostic biomarker, but may also reflect the immune status of LIHC patients.…”

Section: Discussionmentioning

confidence: 76%

Elevated Expression of PDZD11 Is Associated With Poor Prognosis and Immune Infiltrates in Hepatocellular Carcinoma

Yao

Xie

et al. 2021

Front. Genet.

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Epithelial cells are held together by tight and adherent junctions, which are destroyed by the activation of epithelial-to-mesenchymal transition (EMT). The PLEKHA7-PDZD11 complex has been reported to be important for epithelial cell adhesion and connecting tissues. However, there is no research regarding the expression and role of PDZD11 in liver hepatocellular carcinoma (LIHC) progression. Here, we analyzed PDZD11 mRNA expression and its clinical results in LIHC patient RNA sequencing data based on different open databases. Furthermore, we examined differences in PDZD11 expression in LIHC tissues and cell lines using western blotting and real-time qPCR. These results are the first to report that the mRNA and protein levels of PDZD11 are significantly overexpressed in LIHC. Moreover, high expression of PDZD11 was correlated with poor overall survival in patients with LIHC. Gene regulatory network analysis suggested that PDZD11 is mainly involved in copper ion homeostasis, proteasome, and oxidative phosphorylation pathways. Interestingly, we found that PDZD11 levels were positively correlated with the abundance of immune infiltrates. In particular, higher infiltration levels of CD4+ T cells and macrophage subsets significantly affected LIHC patient prognosis. Taken together, these results demonstrate that PDZD11 could be a potential diagnostic and prognostic biomarker in LIHC.

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Enhanced glutamine uptake influences composition of immune cell infiltrates in breast cancer

Cited by 41 publications

References 59 publications

Targeting SLC1A5 and SLC3A2/SLC7A5 as a Potential Strategy to Strengthen Anti-Tumor Immunity in the Tumor Microenvironment

Targeting SLC1A5 and SLC3A2/SLC7A5 as a Potential Strategy to Strengthen Anti-Tumor Immunity in the Tumor Microenvironment

Modulating the Crosstalk between the Tumor and the Microenvironment Using SiRNA: A Flexible Strategy for Breast Cancer Treatment

Elevated Expression of PDZD11 Is Associated With Poor Prognosis and Immune Infiltrates in Hepatocellular Carcinoma

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