bims-trytim 2024-06-23 papers

Issue of 2024–06–23
six papers selected by
Jialin Feng, University of Dundee

Cancer Lett. 2024 Jun 19. pii: S0304-3835(24)00471-3. [Epub ahead of print] 217076

Metabolic Reprogramming in Tumor Immune Microenvironment: Impact on Immune Cell Function and Therapeutic Implications.

Yuqiang Liu, Yu Zhao, Huisheng Song, Yunting Li, Zihao Liu, Zhiming Ye, Jianzhu Zhao, Yuzheng Wu, Jun Tang, Maojin Yao.

Understanding of the metabolic reprogramming has revolutionized our insights into tumor progression and potential treatment. This review concentrates on the aberrant metabolic pathways in cancer cells within the tumor microenvironment (TME). Cancer cells differ from normal cells in their metabolic processing of glucose, amino acids, and lipids in order to adapt to heightened biosynthetic and energy needs. These metabolic shifts, which crucially alter lactic acid, amino acid and lipid metabolism, affect not only tumor cell proliferation but also TME dynamics. This review also explores the reprogramming of various immune cells in the TME. From a therapeutic standpoint, targeting these metabolic alterations represents a novel cancer treatment strategy. This review also discusses approaches targeting the regulation of metabolism of different nutrients in tumor cells and influencing the tumor microenvironment to enhance the immune response. In summary, this review summarizes metabolic reprogramming in cancer and its potential as a target for innovative therapeutic strategies, offering fresh perspectives on cancer treatment.

Keywords: Immune cell; Immunotherapy; Tumor metabolic reprogramming; Tumor microenvironment

DOI: https://doi.org/10.1016/j.canlet.2024.217076

bioRxiv. 2024 Jun 06. pii: 2024.06.05.597474. [Epub ahead of print]

Glioma-derived M-CSF and IL-34 license M-MDSCs to suppress CD8 + T cells in a NOS-dependent manner.

Gregory P Takacs, Julia S Garcia, Caitlyn A Hodges, Christian J Kreiger, Alexandra Sherman, Jeffrey K Harrison.

Glioblastoma (GBM) is the most common malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a subset of myeloid cells, expressing monocytic (M)-MDSC markers and dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate the TME. This study evaluated the mechanism of CCR2 + /CX3CR1 + M-MDSC differentiation and T cell suppressive function in murine glioma models. We determined that bone marrow-derived CCR2 + /CX3CR1 + cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Glioma secreted CSF1R ligands M-CSF and IL-34 were identified as key drivers of M-MDSC differentiation while adenosine and iNOS pathways were implicated in M-MDSC suppression of T cells. Mining a human GBM spatial RNAseq database revealed a variety of different pathways that M-MDSCs utilize to exert their suppressive function that are driven by complex niches within the microenvironment. These data provide a more comprehensive understanding of the mechanism of M-MDSCs in glioblastoma.
Simple Summary: Currently there are no effective therapies for glioblastoma. Infiltrating myeloid cells contribute significantly to the immune suppressive tumor microenvironment that is characteristic of GBM. Monocytic myeloid derived suppressor cells are chief immune suppressive cells found in the glioma microenvironment. Understanding the mechanisms of M-MDSC differentiation and T cell suppression is imperative for generating therapies that target this tumor supportive cell population. In this study we found that glioma secreted CSF1R ligands, M-CSF and IL-34, license M-MDSCs to suppress CD8 T cells. These M-MDSCs partially utilize nitric oxide synthase to illicit their suppressive activity. However, spatial RNAseq points to glioma microenvironment niches driving M-MDSC heterogeneity. Our findings identify key regulators of differentiation and suppressive mechanisms of M-MDSCs and confirm the importance of targeting this cell population in glioma.

DOI: https://doi.org/10.1101/2024.06.05.597474

Int Immunol. 2024 Jun 13. pii: dxae035. [Epub ahead of print]

The tryptophan metabolic pathway of the microbiome and host cells in health and disease.

Kentaro Miyamoto, Tomohisa Sujino, Takanori Kanai.

The intricate and dynamic tryptophan (Trp) metabolic pathway in both the microbiome and host cells highlights its profound implications for health and disease. This pathway involves complex interactions between host cellular and bacteria processes, producing bioactive compounds such as 5-Hydroxytryptamine (5-HT) and kynurenine (Kyn) derivatives. Immune responses to Trp metabolites through specific receptors have been explored, highlighting the role of the aryl hydrocarbon receptor (AHR) in inflammation modulation. Dysregulation of this pathway is implicated in various diseases, such as Alzheimer's and Parkinson's diseases, mood disorders, neuronal diseases, autoimmune diseases such as multiple sclerosis (MS), and cancer. In this article, we describe the impact of the 5-HT, Trp, indole, and Trp metabolites on health and disease. Further, we review the impact of microbiome-derived Trp metabolites that affect immune responses and contribute to maintaining homeostasis, especially in an experimental autoimmune encephalitis (EAE) model of MS.

Keywords: Brain disease; GPR35; Immune cell; Kynurenic acid

DOI: https://doi.org/10.1093/intimm/dxae035

Int J Mol Sci. 2024 May 21. pii: 5584. [Epub ahead of print]25(11):

The Role of Metabolic Reprogramming in the Tumor Immune Microenvironment: Mechanisms and Opportunities for Immunotherapy in Hepatocellular Carcinoma.

Nan Hu, Haiyang Li, Changcheng Tao, Ting Xiao, Weiqi Rong.

As one of the emerging hallmarks of tumorigenesis and tumor progression, metabolic remodeling is common in the tumor microenvironment. Hepatocellular carcinoma (HCC) is the third leading cause of global tumor-related mortality, causing a series of metabolic alterations in response to nutrient availability and consumption to fulfill the demands of biosynthesis and carcinogenesis. Despite the efficacy of immunotherapy in treating HCC, the response rate remains unsatisfactory. Recently, research has focused on metabolic reprogramming and its effects on the immune state of the tumor microenvironment, and immune response rate. In this review, we delineate the metabolic reprogramming observed in HCC and its influence on the tumor immune microenvironment. We discuss strategies aimed at enhancing response rates and overcoming immune resistance through metabolic interventions, focusing on targeting glucose, lipid, or amino acid metabolism, as well as systemic regulation.

Keywords: hepatocellular carcinoma; immunotherapy; metabolic intervention; metabolic reprogramming; tumor microenvironment

DOI: https://doi.org/10.3390/ijms25115584

Int Immunopharmacol. 2024 Jun 14. pii: S1567-5769(24)00921-4. [Epub ahead of print]137 112401

The role of JMJD2A in immune evasion and malignant behavior of esophageal squamous cell carcinoma.

Xiangyu Su, Xu Ding, Chenxi Ding, Guoqing Wang, Chenchun Fu, Fei Liu, Jinjun Shi, Wei He.

OBJECTIVE: This study aimed to investigate the role of JMJD2A in radiotherapy tolerance of esophageal squamous cell carcinoma (ESCC).
METHODS: The levels of H3K9me3 modification were analyzed in anti-PD-1 therapy non-responder or responder patients, and the expression differences of H3K9me3-related modifying enzymes were assessed in TCGA-ESCC and ICGC cohorts. Subsequently, JMJD2A was knocked down in ESCC cells using CRISPR-Cas9 or lentivirus-mediated shRNA, and changes in malignant behavior of ESCC cells were observed. RNA-seq, ATAC-seq, and ChIP-seq analyses were then conducted to investigate the genes and downstream signaling pathways regulated by JMJD2A, and functional validation experiments were performed to analyze the role of downstream regulated genes and pathways in ESCC malignant behavior and immune evasion.
RESULTS: JMJD2A was significantly overexpressed in ESCC and anti-PD-1 therapy non-responders. Knockdown or deletion of JMJD2A significantly promoted the malignant behavior and immune evasion of ESCC. JMJD2A facilitated the structural changes in chromatin and promoted the binding of SMARCA4 to super-enhancers, thereby inducing the expression of GPX4. This resulted in the inhibition of radiation-induced DNA damage and cell ferroptosis, ultimately promoting the malignant behavior and immune evasion of ESCC cells.
CONCLUSION: JMJD2A plays an indispensable role in the malignant behavior and immune evasion of ESCC. It regulates the binding of SMARCA4 to super-enhancers and affects the chromatin's epigenetic landscape, thereby promoting the expression of GPX4 and attenuating iron-mediated cell death caused by radiotherapy. Consequently, it triggers the malignant behavior and immune evasion of ESCC cells.

Keywords: Esophageal squamous cell carcinoma; Ferroptosis; Immune evasion; JMJD2A; Malignant behavior; SMARCA4

DOI: https://doi.org/10.1016/j.intimp.2024.112401

Mini Rev Med Chem. 2024 Jun 14.

Recent Progress of Glutathione Peroxidase 4 Inhibitors in Cancer Therapy.

Shangde Liu, Jian Wang.

Ferroptosis is a novel type of programmed cell death that relies on the build-up of intracellular iron and leads to an increase in toxic lipid peroxides. Glutathione Peroxidase 4 (GPX4) is a crucial regulator of ferroptosis that uses glutathione as a cofactor to detoxify cellular lipid peroxidation. Targeting GPX4 in cancer could be a promising strategy to induce ferroptosis and kill drugresistant cancers effectively. Currently, research on GPX4 inhibitors is of increasing interest in the field of anti-tumor agents. Many reviews have summarized the regulation and ferroptosis induction of GPX4 in human cancer and disease. However, insufficient attention has been paid to GPX4 inhibitors. This article outlines the molecular structures and development prospects of GPX4 inhibitors as novel anticancer agents.

Keywords: Cancer therapy; Covalence; Ferroptosis; GPX4 inhibitor; Prodrug; Selenocysteine

DOI: https://doi.org/10.2174/0113895575308546240607073310