bims-mecami 2023-11-19 papers

Issue of 2023–11–19
four papers selected by
Oltea Sampetrean, Keio University

iScience. 2023 Nov 17. 26(11): 108188

Metabolic predictors of response to immune checkpoint blockade therapy.

Metabolism of immune cells in the tumor microenvironment (TME) plays a critical role in cancer patient response to immune checkpoint inhibitors (ICI). Yet, a metabolic characterization of immune cells in the TME of patients treated with ICI is lacking. To bridge this gap we performed a semi-supervised analysis of ∼1700 metabolic genes using single-cell RNA-seq data of > 1 million immune cells from ∼230 samples of cancer patients treated with ICI. When clustering cells based on their metabolic gene expression, we found that similar immunological cellular states are found in different metabolic states. Most importantly, we found metabolic states that are significantly associated with patient response. We then built a metabolic predictor based on a dozen gene signature, which significantly differentiates between responding and non-responding patients across different cancer types (AUC = 0.8-0.92). Taken together, our results demonstrate the power of metabolism in predicting patient response to ICI.

Keywords: Cancer; Human metabolism; Immunology

DOI: https://doi.org/10.1016/j.isci.2023.108188

J Transl Med. 2023 Nov 15. 21(1): 815

Macrophage metabolism, phenotype, function, and therapy in hepatocellular carcinoma (HCC).

Jingquan Huang, Qiulin Wu, David A Geller, Yihe Yan.

The pivotal role of the tumor microenvironment (TME) in the initiation and advancement of hepatocellular carcinoma (HCC) is widely acknowledged, as it fosters the proliferation and metastasis of HCC cells. Within the intricate TME of HCC, tumor-associated macrophages (TAMs) represent a significant constituent of non-malignant cells. TAMs engage in direct communication with cancer cells in HCC, while also exerting influence on other immune cells to adopt a tumor-supportive phenotype that facilitates tumor progression. Among the multifaceted mechanisms at play, the metabolic reprogramming of both tumor cells and macrophages leads to phenotypic alterations and functional modifications in macrophages. This comprehensive review elucidates the intricate interplay between cellular metabolism and macrophage phenotype/polarization, while also providing an overview of the associated signaling molecules and potential therapeutic strategies for HCC.

Keywords: Function; Hepatocellular carcinoma; Macrophage; Metabolism; Phenotype; Tumor microenvironment

DOI: https://doi.org/10.1186/s12967-023-04716-0

Front Immunol. 2023 ;14 1284344

Histone lactylation regulates cancer progression by reshaping the tumor microenvironment.

Junxing Qu, Peizhi Li, Zhiheng Sun.

As a major product of glycolysis and a vital signaling molecule, many studies have reported the key role of lactate in tumor progression and cell fate determination. Lactylation is a newly discovered post-translational modification induced by lactate. On the one hand, lactylation introduced a new era of lactate metabolism in the tumor microenvironment (TME), and on the other hand, it provided a key breakthrough point for elucidation of the interaction between tumor metabolic reprogramming and epigenetic modification. Studies have shown that the lactylation of tumor cells, tumor stem cells and tumor-infiltrating immune cells in TME can participate in the development of cancer through downstream transcriptional regulation, and is a potential and promising tumor treatment target. This review summarized the discovery and effects of lactylation, as well as recent research on histone lactylation regulating cancer progression through reshaping TME. We also focused on new strategies to enhance anti-tumor effects via targeting lactylation. Finally, we discussed the limitations of existing studies and proposed new perspectives for future research in order to further explore lactylation targets. It may provide a new way and direction to improve tumor prognosis.

Keywords: cancer therapy; epigenetic modification; immune cells; lactylation; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2023.1284344

medRxiv. 2023 Oct 25. pii: 2023.10.24.23297489. [Epub ahead of print]

Rewiring of cortical glucose metabolism fuels human brain cancer growth.

The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), lose aspects of normal biology and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to fuel these processes is poorly understood. Here we perform infusions of 13 C-labeled glucose into patients and mice with brain cancer to define the metabolic fates of glucose-derived carbon in tumor and cortex. By combining these measurements with quantitative metabolic flux analysis, we find that human cortex funnels glucose-derived carbons towards physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. In contrast, brain cancers downregulate these physiologic processes, scavenge alternative carbon sources from the environment, and instead use glucose-derived carbons to produce molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary modulation selectively alters GBM metabolism and slows tumor growth.
Significance: This study is the first to directly measure biosynthetic flux in both glioma and cortical tissue in human brain cancer patients. Brain tumors rewire glucose carbon utilization away from oxidation and neurotransmitter production towards biosynthesis to fuel growth. Blocking these metabolic adaptations with dietary interventions slows brain cancer growth with minimal effects on cortical metabolism.

DOI: https://doi.org/10.1101/2023.10.24.23297489