bims-mecami 2023-03-12 papers

Issue of 2023–03–12
seven papers selected by
Oltea Sampetrean, Keio University

Front Immunol. 2023 ;14 1114582

The role of AMPK in cancer metabolism and its impact on the immunomodulation of the tumor microenvironment.

Chenicheri Kizhakkeveettil Keerthana, Tennyson Prakash Rayginia, Sadiq Chembothumparambil Shifana, Nikhil Ponnoor Anto, Kalishwaralal Kalimuthu, Noah Isakov, Ruby John Anto.

Adenosine monophosphate-activated protein kinase (AMPK) is a key metabolic sensor that is pivotal for the maintenance of cellular energy homeostasis. AMPK contributes to diverse metabolic and physiological effects besides its fundamental role in glucose and lipid metabolism. Aberrancy in AMPK signaling is one of the determining factors which lead to the development of chronic diseases such as obesity, inflammation, diabetes, and cancer. The activation of AMPK and its downstream signaling cascades orchestrate dynamic changes in the tumor cellular bioenergetics. It is well documented that AMPK possesses a suppressor role in the context of tumor development and progression by modulating the inflammatory and metabolic pathways. In addition, AMPK plays a central role in potentiating the phenotypic and functional reprogramming of various classes of immune cells which reside in the tumor microenvironment (TME). Furthermore, AMPK-mediated inflammatory responses facilitate the recruitment of certain types of immune cells to the TME, which impedes the development, progression, and metastasis of cancer. Thus, AMPK appears to play an important role in the regulation of anti-tumor immune response by regulating the metabolic plasticity of various immune cells. AMPK effectuates the metabolic modulation of anti-tumor immunity via nutrient regulation in the TME and by virtue of its molecular crosstalk with major immune checkpoints. Several studies including that from our lab emphasize on the role of AMPK in regulating the anticancer effects of several phytochemicals, which are potential anticancer drug candidates. The scope of this review encompasses the significance of the AMPK signaling in cancer metabolism and its influence on the key drivers of immune responses within the TME, with a special emphasis on the potential use of phytochemicals to target AMPK and combat cancer by modulating the tumor metabolism.

Keywords: AMPK signaling; T cells; cancer metabolism; immune checkpoints; immune response; macrophages; phytochemicals; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2023.1114582

Cancers (Basel). 2023 Feb 28. pii: 1519. [Epub ahead of print]15(5):

Metabolic Barriers to Glioblastoma Immunotherapy.

Nikita Choudhary, Robert C Osorio, Jun Y Oh, Manish K Aghi.

Glioblastoma (GBM) is the most common primary brain tumor with a poor prognosis with the current standard of care treatment. To address the need for novel therapeutic options in GBM, immunotherapies which target cancer cells through stimulating an anti-tumoral immune response have been investigated in GBM. However, immunotherapies in GBM have not met with anywhere near the level of success they have encountered in other cancers. The immunosuppressive tumor microenvironment in GBM is thought to contribute significantly to resistance to immunotherapy. Metabolic alterations employed by cancer cells to promote their own growth and proliferation have been shown to impact the distribution and function of immune cells in the tumor microenvironment. More recently, the diminished function of anti-tumoral effector immune cells and promotion of immunosuppressive populations resulting from metabolic alterations have been investigated as contributory to therapeutic resistance. The GBM tumor cell metabolism of four nutrients (glucose, glutamine, tryptophan, and lipids) has recently been described as contributory to an immunosuppressive tumor microenvironment and immunotherapy resistance. Understanding metabolic mechanisms of resistance to immunotherapy in GBM can provide insight into future directions targeting the anti-tumor immune response in combination with tumor metabolism.

Keywords: glioblastoma; glutamine metabolism; glycolysis; immunotherapy; lipid metabolism; metabolism; tryptophan metabolism; tumor microenvironment

DOI: https://doi.org/10.3390/cancers15051519

Cancers (Basel). 2023 Mar 03. pii: 1588. [Epub ahead of print]15(5):

The Impact of Gut Microbiota-Derived Metabolites on the Tumor Immune Microenvironment.

Maik Luu, Burkhard Schütz, Matthias Lauth, Alexander Visekruna.

Prevention of the effectiveness of anti-tumor immune responses is one of the canonical cancer hallmarks. The competition for crucial nutrients within the tumor microenvironment (TME) between cancer cells and immune cells creates a complex interplay characterized by metabolic deprivation. Extensive efforts have recently been made to understand better the dynamic interactions between cancer cells and surrounding immune cells. Paradoxically, both cancer cells and activated T cells are metabolically dependent on glycolysis, even in the presence of oxygen, a metabolic process known as the Warburg effect. The intestinal microbial community delivers various types of small molecules that can potentially augment the functional capabilities of the host immune system. Currently, several studies are trying to explore the complex functional relationship between the metabolites secreted by the human microbiome and anti-tumor immunity. Recently, it has been shown that a diverse array of commensal bacteria synthetizes bioactive molecules that enhance the efficacy of cancer immunotherapy, including immune checkpoint inhibitor (ICI) treatment and adoptive cell therapy with chimeric antigen receptor (CAR) T cells. In this review, we highlight the importance of commensal bacteria, particularly of the gut microbiota-derived metabolites that are capable of shaping metabolic, transcriptional and epigenetic processes within the TME in a therapeutically meaningful way.

Keywords: cancer immunotherapy; commensal bacteria; intratumoral microbiota; microbiota-derived metabolites; oncobiome; tumor microenvironment (TME)

DOI: https://doi.org/10.3390/cancers15051588

Semin Cancer Biol. 2023 Mar 03. pii: S1044-579X(23)00034-2. [Epub ahead of print]

The metabolic crosstalk between PIN1 and the tumour microenvironment.

Isabella Caligiuri, Canzonieri Vincenzo, Tomochiro Asano, Vinit Kumar, Flavio Rizzolio.

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) is a member of a family of peptidyl-prolyl isomerases that specifically recognizes and binds phosphoproteins, catalyzing the rapid cis-trans isomerization of phosphorylated serine/threonine-proline motifs, which leads to changes in the structures and activities of the targeted proteins. Through this complex mechanism, PIN1 regulates many hallmarks of cancer including cell autonomous metabolism and the crosstalk with the cellular microenvironment. Many studies showed that PIN1 is largely overexpressed in cancer turning on a set of oncogenes and abrogating the function of tumor suppressor genes. Among these targets, recent evidence demonstrated that PIN1 is involved in lipid and glucose metabolism and accordingly, in the Warburg effect, a characteristic of tumor cells. As an orchestra master, PIN1 finely tunes the signaling pathways allowing cancer cells to adapt and take advantage from a poorly organized tumor microenvironment. In this review, we highlight the trilogy among PIN1, the tumor microenvironment and the metabolic program rewiring.

Keywords: Cancer; Metabolism; Molecular Signaling; PIN1; Tumor Microenvironment

DOI: https://doi.org/10.1016/j.semcancer.2023.03.001

Cell Metab. 2023 Mar 06. pii: S1550-4131(23)00049-9. [Epub ahead of print]

Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity.

The metabolic state represents a major hurdle for an effective adoptive T cell therapy (ACT). Indeed, specific lipids can harm CD8+ T cell (CTL) mitochondrial integrity, leading to defective antitumor responses. However, the extent to which lipids can affect the CTL functions and fate remains unexplored. Here, we show that linoleic acid (LA) is a major positive regulator of CTL activity by improving metabolic fitness, preventing exhaustion, and stimulating a memory-like phenotype with superior effector functions. We report that LA treatment enhances the formation of ER-mitochondria contacts (MERC), which in turn promotes calcium (Ca2+) signaling, mitochondrial energetics, and CTL effector functions. As a direct consequence, the antitumor potency of LA-instructed CD8 T cells is superior in vitro and in vivo. We thus propose LA treatment as an ACT potentiator in tumor therapy.

Keywords: CD8 T cells; adoptive T cell therapy; linoleic acid; lipid metabolism; metabolic fitness

DOI: https://doi.org/10.1016/j.cmet.2023.02.013

J Clin Invest. 2023 Mar 09. pii: e164348. [Epub ahead of print]

Intercellular HIF1a reprogams mammary progenitors and myeloid immune evasion to drive high-risk breast lesions.

Irene Bertolini, Michela Perego, Yulia Nefedova, Cindy Lin, Andrew T Milcarek, Peter Vogel, Jagadish C Ghosh, Andrew V Kossenkov, Dario C Altieri.

The origin of breast cancer, whether primary or recurrent, is unknown. Here, we show that invasive breast cancer cells exposed to hypoxia release small extracellular vesicles (sEV) that disrupt the differentiation of normal mammary epithelia, expand stem and luminal progenitor cells, and induce atypical ductal hyperplasia and intraepithelial neoplasia. This was accompanied by systemic immunosuppression with increased myeloid cell release of the "alarmin", S100A9, and oncogenic traits of EMT, angiogenesis, and local and disseminated luminal cell invasion, in vivo. In the presence of a mammary gland driver oncogene (MMTV-PyMT), hypoxic sEV accelerated bilateral breast cancer onset and progression. Mechanistically, genetic or pharmacologic targeting of hypoxia-inducible factor-1α (HIF1α) packaged in hypoxic sEV, or homozygous deletion of S100A9 normalized mammary gland differentiation, restored T cell function and prevented atypical hyperplasia. The transcriptome of sEV-induced mammary gland lesions resembled luminal breast cancer, and detection of HIF1α in plasma circulating sEV from luminal breast cancer patients correlated with disease recurrence. Therefore, sEV-HIF1α signaling drives both local and systemic mechanisms of mammary gland transformation at high risk for evolution to multifocal breast cancer. This pathway may provide a readily accessible biomarker of luminal breast cancer progression.

Keywords: Breast cancer; Cell Biology; Hypoxia; Neutrophils; Oncology

DOI: https://doi.org/10.1172/JCI164348