bims-mecami 2024-09-29 papers

Issue of 2024–09–29
five papers selected by
Oltea Sampetrean, Keio University

Nat Immunol. 2024 Oct;25(10): 1884-1899

Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy.

Geoffrey J Markowitz, Yi Ban, Diamile A Tavarez, Liron Yoffe, Enrique Podaza, Yongfeng He, Mitchell T Martin, Michael J P Crowley, Tito A Sandoval, Dingcheng Gao, M Laura Martin, Olivier Elemento, Juan R Cubillos-Ruiz, Timothy E McGraw, Nasser K Altorki, Vivek Mittal.

TCF1high progenitor CD8+ T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1high progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2KO CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling as determined by 1,2-13C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8+ T cells toward a TCF1high population, generated a unique transcriptional landscape and adoptive transfer of agonist-treated CD8+ T cells enhanced tumor control in mice in combination with PD-1 blockade and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state promoting immunotherapy efficacy.

DOI: https://doi.org/10.1038/s41590-024-01963-1

Trends Endocrinol Metab. 2024 Sep 19. pii: S1043-2760(24)00244-3. [Epub ahead of print]

Metabolic reprogramming of macrophages in cancer therapy.

Xudong Wang, Shaolong Zhang, Dixuan Xue, Dante Neculai, Jin Zhang.

Cancer presents a significant global public health challenge. Within the tumor microenvironment (TME), macrophages are the most abundant immune cell population. Tumor-associated macrophages (TAMs) undergo metabolic reprogramming through influence of the TME; thus, by manipulating key metabolic pathways such as glucose, lipid, or amino acid metabolism, it may be possible to shift TAMs towards an antitumor state, enhancing the immune response against tumors. Here, we highlight the metabolic reprogramming of macrophages as a potential approach for cancer immunotherapy. We explore the major pathways involved in the metabolic reprogramming of TAMs and offer new and valuable insights on the current technologies utilized for TAM reprogramming, including genome editing, antibodies, small molecules, nanoparticles and other in situ editing strategies.

Keywords: cancer therapy; macrophage; metabolic reprogramming; tumor microenvironment

DOI: https://doi.org/10.1016/j.tem.2024.08.009

JCI Insight. 2024 Aug 13. pii: e180114. [Epub ahead of print]9(18):

Metabolic landscape of the healthy pancreas and pancreatic tumor microenvironment.

Monica E Bonilla, Megan D Radyk, Matthew D Perricone, Ahmed M Elhossiny, Alexis C Harold, Paola I Medina-Cabrera, Padma Kadiyala, Jiaqi Shi, Timothy L Frankel, Eileen S Carpenter, Michael D Green, Cristina Mitrea, Costas A Lyssiotis, Marina Pasca di Magliano.

Pancreatic cancer, one of the deadliest human malignancies, is characterized by a fibro-inflammatory tumor microenvironment and wide array of metabolic alterations. To comprehensively map metabolism in a cell type-specific manner, we harnessed a unique single-cell RNA-sequencing dataset of normal human pancreata. This was compared with human pancreatic cancer samples using a computational pipeline optimized for this study. In the cancer cells we observed enhanced biosynthetic programs. We identified downregulation of mitochondrial programs in several immune populations, relative to their normal counterparts in healthy pancreas. Although granulocytes, B cells, and CD8+ T cells all downregulated oxidative phosphorylation, the mechanisms by which this occurred were cell type specific. In fact, the expression pattern of the electron transport chain complexes was sufficient to identify immune cell types without the use of lineage markers. We also observed changes in tumor-associated macrophage (TAM) lipid metabolism, with increased expression of enzymes mediating unsaturated fatty acid synthesis and upregulation in cholesterol export. Concurrently, cancer cells exhibited upregulation of lipid/cholesterol receptor import. We thus identified a potential crosstalk whereby TAMs provide cholesterol to cancer cells. We suggest that this may be a new mechanism boosting cancer cell growth and a therapeutic target in the future.

Keywords: Bioinformatics; Cancer; Macrophages; Oncology

DOI: https://doi.org/10.1172/jci.insight.180114

Drug Discov Today. 2024 Sep 19. pii: S1359-6446(24)00314-3. [Epub ahead of print]29(11): 104189

MAT2A inhibition combats metabolic and transcriptional reprogramming in cancer.

Fadi E Pulous, Barbara Steurer, Frank W Pun, Man Zhang, Feng Ren, Alex Zhavoronkov.

Metabolic and transcriptional reprogramming are crucial hallmarks of carcinogenesis that present exploitable vulnerabilities for the development of targeted anticancer therapies. Through controlling the balance of the cellular methionine (MET) metabolite pool, MET adenosyl transferase 2 alpha (MAT2A) regulates crucial steps during metabolism and the epigenetic control of transcription. The aberrant function of MAT2A has been shown to drive malignant transformation through metabolic addiction, transcriptional rewiring, and immune modulation of the tumor microenvironment (TME). Moreover, MAT2A sustains the survival of 5'-methylthioadenosine phosphorylase (MTAP)-deficient tumors, conferring synthetic lethality to cancers with MTAP loss, a genetic alteration that occurs in ∼15% of all cancers. Thus, the pharmacological inhibition of MAT2A is emerging as a desirable therapeutic strategy to combat tumor growth. Here, we review the latest insights into MAT2A biology, focusing on its roles in both metabolic addiction and gene expression modulation in the TME, outline the current landscape of MAT2A inhibitors, and highlight the most recent clinical developments and opportunities for MAT2A inhibition as a novel anti-tumor therapy.

Keywords: MAT2A and MTAP synthetic lethality; MAT2A-driven tumor progression; MTAP-null cancers; cancer cell metabolism; methionine synthesis

DOI: https://doi.org/10.1016/j.drudis.2024.104189

FEBS J. 2024 Sep 22.

Harnessing nucleotide metabolism and immunity in cancer: a tumour microenvironment perspective.

Hadil Sulieman, Alexandra Emerson, Peter M Wilson, Karl A Mulligan, Robert D Ladner, Melissa J LaBonte.

The tumour microenvironment (TME) is a dynamic nexus where cancer cell metabolism and the immune system intricately converge, with nucleotide metabolism (NM) playing a pivotal role. This review explores the critical function of NM in cancer cell proliferation and its profound influence on the TME and immune landscape. NM is essential for DNA and RNA synthesis and is markedly upregulated in cancer cells to meet the demands of rapid growth. This metabolic rewiring fuels cancer progression, but also shapes the TME, impacting the function and viability of immune cells. The altered nucleotide milieu in the TME can suppress immune response, aiding cancer cell evasion from immune surveillance. Drug discoveries in the field of NM have revealed different therapeutic strategies, including inhibitors of nucleotide synthesis and drugs targeting salvage pathways, which are discussed thoroughly in this review. Furthermore, the emerging strategy of combining NM-targeted therapies with immunotherapies is emphasised, particularly their effect on sensitising tumours to immune checkpoint inhibitors and enhancing overall treatment efficacy. The Human Genome Project paved the way for personalised medicine, countering the established 'one size fits all' approach to cancer treatment. Advances in understanding the TME and NM have spurred interest in personalised therapeutic strategies. This review highlights the potential of leveraging individual tumour metabolic profiles to guide treatment selection, aiming to optimise efficacy and minimise adverse effects. The strategic importance of targeting NM in cancer therapy and its synergistic potential with immunotherapies offers a path towards more effective and personalised cancer treatments.

Keywords: cancer immunology; immune checkpoint inhibitors; immunometabolism; metabolic therapies; nucleotide metabolism; purine metabolism; pyrimidine synthesis; therapeutic modulation; tumour microenvironment

DOI: https://doi.org/10.1111/febs.17278