bims-mepmim 2024-12-01 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2024–12–01
twenty papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism

ACSS1-dependent acetate utilization rewires mitochondrial metabolism to support AML and melanoma tumor growth and metastasis.
Fungal symbiont transmitted by free-living mice promotes type 2 immunity.
Glucose limitation protects cancer cells from apoptosis induced by pyrimidine restriction and replication inhibition.
Macrophages and nociceptor neurons form a sentinel unit around fenestrated capillaries to defend the synovium from circulating immune challenge.
IFN-γ-dependent regulation of intestinal epithelial homeostasis by NKT cells.
The redox sensor KEAP1 facilitates adaptation of T cells to chronic antigen stimulation by preventing hyperactivation.
The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness.
Coordination between the eIF2 kinase GCN2 and p53 signaling supports purine metabolism and the progression of prostate cancer.
NFE2L2 and SLC25A39 drive cuproptosis resistance through GSH metabolism.
Interleukin-2-secreting T helper cells promote extra-follicular B cell maturation via intrinsic regulation of a B cell mTOR-AKT-Blimp-1 axis.
Nucleo-cytosolic acetyl-CoA drives tumor immune evasion by regulating PD-L1 in melanoma.
ACSL4 and polyunsaturated lipids support metastatic extravasation and colonization.
Cancer cells impair monocyte-mediated T cell stimulation to evade immunity.
The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk.
Endothelial eNOS deficiency causes podocyte injury through NFAT2 and heparanase in diabetic mice.
Mouse and human macrophages and their roles in cardiovascular health and disease.
Childhood-onset lupus nephritis is characterized by complex interactions between kidney stroma and infiltrating immune cells.
PGC-1α drives small cell neuroendocrine cancer progression toward an ASCL1-expressing subtype with increased mitochondrial capacity.
Patient-derived tumor organoid and fibroblast assembloid models for interrogation of the tumor microenvironment in esophageal adenocarcinoma.
Macrophages are activated toward phagocytic lymphoma cell clearance by pentose phosphate pathway inhibition.

Cell Rep. 2024 Nov 21. pii: S2211-1247(24)01339-1. [Epub ahead of print]43(12): 114988

ACSS1-dependent acetate utilization rewires mitochondrial metabolism to support AML and melanoma tumor growth and metastasis.

Sabina I Hlavaty, Kelsey N Salcido, Katherine A Pniewski, Dzmitry Mukha, Weili Ma, Toshitha Kannan, Joel Cassel, Yellamelli V V Srikanth, Qin Liu, Andrew Kossenkov, Joseph M Salvino, Qing Chen, Zachary T Schug.

  Cancer cells often use alternative nutrient sources to support their metabolism and proliferation. One important alternative nutrient source for many cancers is acetate. Acetate is metabolized into acetyl-coenzyme A (CoA) by acetyl-CoA synthetases 1 and 2 (ACSS1 and ACSS2), which are found in the mitochondria and cytosol, respectively. We show that ACSS1 and ACSS2 are differentially expressed in cancer. Melanoma, breast cancer, and acute myeloid leukemia cells expressing ACSS1 readily use acetate for acetyl-CoA biosynthesis and to fuel mitochondrial metabolism. ACSS1-dependent acetate metabolism decreases the relative contributions of glucose and glutamine to the tricarboxylic acid (TCA) cycle and alters the pentose phosphate pathway and redox state of cancer cells. ACSS1 knockdown decreases acute myeloid leukemia burden in vivo and inhibits melanoma tumor and metastatic growth. Our study highlights a key role for ACSS1-dependent acetate metabolism for cancer growth, raising the potential for ACSS1-targeting therapies in cancer.

Keywords:  ACSS1; ACSS2; ACSS2 inhibitor; AML; CP: Cancer; CP: Metabolism; acetate; cancer; melanoma; metabolism; metastasis

DOI:  https://doi.org/10.1016/j.celrep.2024.114988
Nature. 2024 Nov 27.

Fungal symbiont transmitted by free-living mice promotes type 2 immunity.

Yun Liao, Iris H Gao, Takato Kusakabe, Woan-Yu Lin, Alexander Grier, Xiangyu Pan, Olga Morzhanaeva, Terrance P Shea, Hiroshi Yano, Danielle Karo-Atar, Kaitlin A Olsen, Ji Hoon Oh, Kurt J Vandegrift, Irah L King, Christina A Cuomo, David Artis, Barbara Rehermann, Neil Lipman, Iliyan D Iliev.

The gut mycobiota is crucial for intestinal homeostasis and immune function1. Yet its variability and inconsistent fungal colonization of laboratory mice hinders the study of the evolutionary and immune processes that underpin commensalism2,3. Here, we show that Kazachstania pintolopesii is a fungal commensal in wild urban and rural mice, with an exceptional ability to colonize the mouse gastrointestinal tract and dominate the gut mycobiome. Kazachstania pintolopesii colonization occurs in a bacteria-independent manner, results in enhanced colonization resistance to other fungi and is shielded from host immune surveillance, allowing commensal presence. Following changes in the mucosal environment, K. pintolopesii colonization triggers a type 2 immune response in mice and induces gastrointestinal eosinophilia. Mechanistically, we determined that K. pintolopesii activates type 2 immunity via the induction of epithelial IL-33 and downstream IL-33-ST2 signalling during mucus fluctuations. Kazachstania pintolopesii-induced type 2 immunity enhanced resistance to helminth infections or aggravated gastrointestinal allergy in a context-dependent manner. Our findings indicate that K. pintolopesii is a mouse commensal and serves as a valuable model organism for studying gut fungal commensalism and immunity in its native host. Its unnoticed presence in mouse facilities highlights the need to evaluate its influence on experimental outcomes and phenotypes.

DOI: https://doi.org/10.1038/s41586-024-08213-2
Nat Metab. 2024 Nov 26.

Glucose limitation protects cancer cells from apoptosis induced by pyrimidine restriction and replication inhibition.

Minwoo Nam, Wenxin Xia, Abdul Hannan Mir, Alexandra Jerrett, Jessica B Spinelli, Tony T Huang, Richard Possemato.

Cancer cells often experience nutrient-limiting conditions because of their robust proliferation and inadequate tumour vasculature, which results in metabolic adaptation to sustain proliferation. Most cancer cells rapidly consume glucose, which is severely reduced in the nutrient-scarce tumour microenvironment. In CRISPR-based genetic screens to identify metabolic pathways influenced by glucose restriction, we find that tumour-relevant glucose concentrations (low glucose) protect cancer cells from inhibition of de novo pyrimidine biosynthesis, a pathway that is frequently targeted by chemotherapy. We identify two mechanisms to explain this result, which is observed broadly across cancer types. First, low glucose limits uridine-5-diphosphate-glucose synthesis, preserving pyrimidine nucleotide availability and thereby prolonging the time to replication fork stalling. Second, low glucose directly modulates apoptosis downstream of replication fork stalling by suppressing BAK activation and subsequent cytochrome c release, key events that activate caspase-9-dependent mitochondrial apoptosis. These results indicate that the low glucose levels frequently observed in tumours may limit the efficacy of specific chemotherapeutic agents, highlighting the importance of considering the effects of the tumour nutrient environment on cancer therapy.

DOI: https://doi.org/10.1038/s42255-024-01166-w
Nat Immunol. 2024 Dec;25(12): 2270-2283

Macrophages and nociceptor neurons form a sentinel unit around fenestrated capillaries to defend the synovium from circulating immune challenge.

Tetsuo Hasegawa, Colin Y C Lee, Andrew J Hotchen, Aaron Fleming, Rahul Singh, Kunimichi Suzuki, Michisuke Yuzaki, Masahiko Watanabe, Mark A Birch, Andrew W McCaskie, Nikolett Lénárt, Krisztina Tóth, Ádám Dénes, Zhaoyuan Liu, Florent Ginhoux, Nathan Richoz, Menna R Clatworthy.

A wide variety of systemic pathologies, including infectious and autoimmune diseases, are accompanied by joint pain or inflammation, often mediated by circulating immune complexes (ICs). How such stimuli access joints and trigger inflammation is unclear. Whole-mount synovial imaging revealed PV1+ fenestrated capillaries at the periphery of the synovium in the lining-sublining interface. Circulating ICs extravasated from these PV1+ capillaries, and nociceptor neurons and three distinct macrophage subsets formed a sentinel unit around them. Macrophages showed subset-specific responses to systemic IC challenge; LYVE1+CX3CR1+ macrophages orchestrated neutrophil recruitment and activated calcitonin gene-related peptide+ (CGRP+) nociceptor neurons via interleukin-1β. In contrast, major histocompatibility complex class II+CD11c+ (MHCII+CD11c+) and MHCII+CD11c- interstitial macrophages formed tight clusters around PV1+ capillaries in response to systemic immune stimuli, a feature enhanced by nociceptor-derived CGRP. Altogether, we identify the anatomical location of synovial PV1+ capillaries and subset-specific macrophage-nociceptor cross-talk that forms a blood-joint barrier protecting the synovium from circulating immune challenges.

DOI: https://doi.org/10.1038/s41590-024-02011-8
Cell Rep. 2024 Nov 23. pii: S2211-1247(24)01299-3. [Epub ahead of print]43(12): 114948

IFN-γ-dependent regulation of intestinal epithelial homeostasis by NKT cells.

Marta Lebrusant-Fernandez, Tom Ap Rees, Rebeca Jimeno, Nikolaos Angelis, Joseph C Ng, Franca Fraternali, Vivian S W Li, Patricia Barral.

  Intestinal homeostasis is maintained through the combined functions of epithelial and immune cells that collaborate to preserve the integrity of the intestinal barrier. However, the mechanisms by which immune cell populations regulate intestinal epithelial cell (IEC) homeostasis remain unclear. Here, we use a multi-omics approach to study the immune-epithelial crosstalk and identify CD1d-restricted natural killer T (NKT) cells as key regulators of IEC biology. We find that NKT cells are abundant in the proximal small intestine and show hallmarks of activation at steady state. Subsequently, NKT cells regulate the survival and the transcriptional and cellular composition landscapes of IECs in intestinal organoids, through interferon-γ (IFN-γ) and interleukin-4 secretion. In vivo, lack of NKT cells results in an increase in IEC turnover, while NKT cell activation leads to IFN-γ-dependent epithelial apoptosis. Our findings propose NKT cells as potent producers of cytokines that contribute to the regulation of IEC homeostasis.

Keywords:  CP: Immunology; IFN-γ; NKT cell; intestinal epithelial cell; intestinal organoids

DOI:  https://doi.org/10.1016/j.celrep.2024.114948
Sci Immunol. 2024 Nov 29. 9(101): eadk2954

The redox sensor KEAP1 facilitates adaptation of T cells to chronic antigen stimulation by preventing hyperactivation.

Ziang Zhu, Ying Luo, Guohua Lou, Kiddist Yihunie, Safuwra Wizzard, Andrew W DeVilbiss, Sarah Muh, Chaoyu Ma, Sejal S Shinde, Jonathan Hoar, Taidou Hu, Nu Zhang, Shyam Biswal, Ralph J DeBerardinis, Tuoqi Wu, Chen Yao.

During persistent antigen stimulation, exhausted CD8+ T cells are continuously replenished by self-renewing stem-like T cells. However, how CD8+ T cells adapt to chronic stimulation remains unclear. Here, we show that persistent antigen stimulation primes chromatin for regulation by the redox-sensing KEAP1-NRF2 pathway. Loss of KEAP1 in T cells impaired control of chronic viral infection. T cell-intrinsic KEAP1 suppressed NRF2 to promote expansion and persistence of virus-specific CD8+ T cells, drive a stem-like T cell response, down-regulate immune checkpoint molecules, and limit T cell receptor (TCR) hyperactivation and apoptosis. NRF2 epigenetically derepressed BACH2 targets and opposed a stem-like program driven by BACH2. In exhausted T cells induced by tonic GD2 chimeric antigen receptor (CAR) signaling, the effects of KEAP1 deficiency were rescued by inhibiting proximal TCR signaling. Enhancing mitochondrial oxidation improved the expansion and survival of KEAP1-deficient CD8+ GD2 CAR T cells and up-regulated markers associated with stem-like cells. Thus, the KEAP1-NRF2 axis regulates stem-like CD8+ T cells and long-term T cell immunity during chronic antigen exposure.

DOI: https://doi.org/10.1126/sciimmunol.adk2954
Nat Commun. 2024 Nov 23. 15(1): 10163

The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness.

Xingxing Zhu, Yue Wu, Yanfeng Li, Xian Zhou, Jens O Watzlawik, Yin Maggie Chen, Ariel L Raybuck, Daniel D Billadeau, Virginia Smith Shapiro, Wolfdieter Springer, Jie Sun, Mark R Boothby, Hu Zeng.

Germinal center (GC) formation, which is an integrant part of humoral immunity, involves energy-consuming metabolic reprogramming. Rag-GTPases are known to signal amino acid availability to cellular pathways that regulate nutrient distribution such as the mechanistic target of rapamycin complex 1 (mTORC1) pathway and the transcription factors TFEB and TFE3. However, the contribution of these factors to humoral immunity remains undefined. Here, we show that B cell-intrinsic Rag-GTPases are critical for the development and activation of B cells. RagA/RagB deficient B cells fail to form GCs, produce antibodies, and to generate plasmablasts during both T-dependent (TD) and T-independent (TI) humoral immune responses. Deletion of RagA/RagB in GC B cells leads to abnormal dark zone (DZ) to light zone (LZ) ratio and reduced affinity maturation. Mechanistically, the Rag-GTPase complex constrains TFEB/TFE3 activity to prevent mitophagy dysregulation and maintain mitochondrial fitness in B cells, which are independent of canonical mTORC1 activation. TFEB/TFE3 deletion restores B cell development, GC formation in Peyer's patches and TI humoral immunity, but not TD humoral immunity in the absence of Rag-GTPases. Collectively, our data establish the Rag GTPase-TFEB/TFE3 pathway as a likely mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells.

DOI: https://doi.org/10.1038/s41467-024-54344-5
Sci Signal. 2024 Nov 26. 17(864): eadp1375

Coordination between the eIF2 kinase GCN2 and p53 signaling supports purine metabolism and the progression of prostate cancer.

Ricardo A Cordova, Noah R Sommers, Andrew S Law, Angela J Klunk, Katherine E Brady, David W Goodrich, Tracy G Anthony, Jeffrey J Brault, Roberto Pili, Ronald C Wek, Kirk A Staschke.

Cancers invoke various pathways to mitigate external and internal stresses to continue their growth and progression. We previously reported that the eIF2 kinase GCN2 and the integrated stress response are constitutively active in prostate cancer (PCa) and are required to maintain amino acid homeostasis needed to fuel tumor growth. However, although loss of GCN2 function reduces intracellular amino acid availability and PCa growth, there is no appreciable cell death. Here, we discovered that the loss of GCN2 in PCa induces prosenescent p53 signaling. This p53 activation occurred through GCN2 inhibition-dependent reductions in purine nucleotides that impaired ribosome biogenesis and, consequently, induced the impaired ribosome biogenesis checkpoint. p53 signaling induced cell cycle arrest and senescence that promoted the survival of GCN2-deficient PCa cells. Depletion of GCN2 combined with loss of p53 or pharmacological inhibition of de novo purine biosynthesis reduced proliferation and enhanced cell death in PCa cell lines, organoids, and xenograft models. Our findings highlight the coordinated interplay between GCN2 and p53 regulation during nutrient stress and provide insight into how they could be targeted in developing new therapeutic strategies for PCa.

DOI: https://doi.org/10.1126/scisignal.adp1375
Sci Rep. 2024 Nov 28. 14(1): 29579

NFE2L2 and SLC25A39 drive cuproptosis resistance through GSH metabolism.

Jiao Liu, Hu Tang, Fangquan Chen, Changfeng Li, Yangchun Xie, Rui Kang, Daolin Tang.

  Cuproptosis is a recently discovered form of regulated cell death triggered by mitochondrial copper accumulation and proteotoxic stress. Here, we provide the first evidence that glutathione (GSH), a major non-protein thiol in cells, acts as a cuproptosis inhibitor in pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, GSH inhibits cuproptosis by chelating copper, contrasting its role in blocking ferroptosis by inhibiting lipid peroxidation. The classical cuproptosis inducer, ES-Cu (elesclomol plus copper), increases the protein stability of the transcription factor NFE2L2 (also known as NRF2), leading to the upregulation of gene expression of glutamate-cysteine ligase modifier subunit (GCLM) and glutamate-cysteine ligase catalytic subunit (GCLC). GCLM and GCLC are rate-limiting enzymes in GSH synthesis, and increased GSH is transported into mitochondria via the solute carrier family 25 member 39 (SLC25A39) transporter. Consequently, genetic inhibition of the NFE2L2-GSH-SLC25A39 pathway enhances cuproptosis-mediated tumor suppression in cell culture and in mouse tumor models. These findings not only reveal distinct mechanisms of GSH in inhibiting cuproptosis and ferroptosis, but also suggest a potential combination strategy to suppress PDAC tumor growth.

Keywords:  Copper; Cuproptosis; Elesclomol; Glutathione; NFE2L2; SLC25A39

DOI:  https://doi.org/10.1038/s41598-024-81317-x
Immunity. 2024 Nov 26. pii: S1074-7613(24)00521-1. [Epub ahead of print]

Interleukin-2-secreting T helper cells promote extra-follicular B cell maturation via intrinsic regulation of a B cell mTOR-AKT-Blimp-1 axis.

Caterina E Faliti, Maria Mesina, Jinyong Choi, Simon Bélanger, Monique A Marshall, Christopher M Tipton, Sakeenah Hicks, Prashanti Chappa, Maria A Cardenas, Mohamed Abdel-Hakeem, Theresa C Thinnes, Christopher Cottrell, Christopher D Scharer, William R Schief, David Nemazee, Matthew C Woodruff, John M Lindner, Ignacio Sanz, Shane Crotty.

  During antigen-driven responses, B cells can differentiate at extra-follicular (EF) sites or initiate germinal centers (GCs) in processes that involve interactions with T cells. Here, we examined the roles of interleukin (IL)-2 secreted by T helper (Th) cells during cognate interactions with activated B cells. IL-2 boosted the expansion of EF plasma cells and the secretion of low-mutated immunoglobulin G (IgG). Conversely, genetically disrupting IL-2 expression by CD4+ T cells, or IL-2 receptor (CD25) expression by B cells, promoted B cell entry into the GC and high-affinity antibody secretion. Mechanistically, IL-2 induced early mTOR activity, expression of the transcriptional regulator IRF4, and metabolic changes in B cells required to form Blimp-1-expressing plasma cells. Thus, T cell help via IL-2 regulates an mTOR-AKT-Blimp-1 axis in activated B cells, providing insight into the mechanisms that determine EF versus GC fates and positioning IL-2 as an early switch controlling plasma cell versus GC B cell commitment.

Keywords:  CD4 T cells; IL-2 cytokine; T follicular helper cells; Tfh cells; antibodies; mTOR; metabolism; plasma cells; vaccine

DOI:  https://doi.org/10.1016/j.immuni.2024.11.006
Cell Rep. 2024 Nov 26. pii: S2211-1247(24)01366-4. [Epub ahead of print]43(12): 115015

Nucleo-cytosolic acetyl-CoA drives tumor immune evasion by regulating PD-L1 in melanoma.

Huina Wang, Xiuli Yi, Xiangxu Wang, Yuqi Yang, Hengxiang Zhang, Hao Wang, Jianru Chen, Baolu Zhang, Sen Guo, Lili Wu, Juan Du, Yuhan Chen, Ningyue Sun, Tianwen Gao, Rui Zhang, Huijie Bian, Lintao Jia, Chunying Li, Weinan Guo.

  Acetyl coenzyme A (acetyl-CoA), a versatile central metabolite, plays a critical role in various metabolic processes and protein acetylation. While its impact on tumor cell properties is well established, the connection between acetyl-CoA metabolism and immune evasion in tumors remains unclear. Here, we uncover a mechanism by which nucleo-cytosolic acetyl-CoA contributes to immune evasion through regulation of programmed death ligand 1 (PD-L1). Specifically, bioinformatics analysis reveals a negative correlation between acetyl-CoA metabolism and anti-tumor immunity across multiple cancers. Inhibition of the acetyl-CoA-producing enzyme ATP-citrate lyase (ACLY) leads to a re-invigoration of cytotoxic T cells and enhances the efficacy of immunotherapy. Mechanistically, nucleo-cytosolic acetyl-CoA promotes PD-L1 transcription via P300-dependent histone H3K27 acetylation at the promoter region of CD274. The ACLY-H3K27ac-PD-L1 axis is verified in clinical specimens and predicts poor immunotherapy response. Our findings suggest that targeting acetyl-CoA metabolism may act as a promising strategy to overcome immune evasion and improve the outcomes of cancer immunotherapy.

Keywords:  ACLY; Acetyl-CoA; CP: Cancer; PD-L1; histone acetylation; immune evasion; melanoma; metabolism

DOI:  https://doi.org/10.1016/j.celrep.2024.115015
Cell. 2024 Nov 19. pii: S0092-8674(24)01270-4. [Epub ahead of print]

ACSL4 and polyunsaturated lipids support metastatic extravasation and colonization.

Yuqi Wang, Mangze Hu, Jian Cao, Fengxiang Wang, Jingrong Regina Han, Tianshu William Wu, Luxiao Li, Jinshi Yu, Yujing Fan, Guanglei Xie, Heyuan Lian, Yueying Cao, Nathchar Naowarojna, Xi Wang, Yilong Zou.

  Metastatic dissemination to distant organs demands that cancer cells possess high morphological and metabolic adaptability. However, contributions of the cellular lipidome to metastasis remain elusive. Here, we uncover a correlation between metastasis potential and ferroptosis susceptibility in multiple cancers. Metastases-derived cancer cells exhibited higher ferroptosis sensitivity and polyunsaturated fatty acyl (PUFA)-lipid contents than primary-tumor-derived cells from ovarian cancer patients. Metabolism-focused CRISPR screens in a mouse model for ovarian cancer distant metastasis established via two rounds of in vivo selection revealed the PUFA-lipid biosynthesis enzyme acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4) as a pro-hematogenous metastasis factor. ACSL4 promotes metastatic extravasation by enhancing membrane fluidity and cellular invasiveness. While promoting metastasis, the high PUFA-lipid state creates dependencies on abhydrolase-domain-containing 6, acylglycerol lipase (ABHD6), enoyl-CoA delta isomerase 1 (ECI1), and enoyl-CoA hydratase 1 (ECH1)-rate-limiting enzymes preparing unsaturated fatty acids (UFAs) for β-oxidation. ACSL4/ECH1 co-inhibition achieved potent suppression of metastasis. Our work establishes the dual functions of PUFA-lipids in tumor progression and metastasis that may be exploitable for therapeutic development.

Keywords:  ACSL4; ECH1; cancer metastasis; extravasation; ferroptosis susceptibility; in vivo CRISPR screens; lipid metabolism; metastatic colonization; ovarian cancer; polyunsaturated lipids

DOI:  https://doi.org/10.1016/j.cell.2024.10.047
Nature. 2024 Nov 27.

Cancer cells impair monocyte-mediated T cell stimulation to evade immunity.

Anais Elewaut, Guillem Estivill, Felix Bayerl, Leticia Castillon, Maria Novatchkova, Elisabeth Pottendorfer, Lisa Hoffmann-Haas, Martin Schönlein, Trung Viet Nguyen, Martin Lauss, Francesco Andreatta, Milica Vulin, Izabela Krecioch, Jonas Bayerl, Anna-Marie Pedde, Naomi Fabre, Felix Holstein, Shona M Cronin, Sarah Rieser, Denarda Dangaj Laniti, David Barras, George Coukos, Camelia Quek, Xinyu Bai, Miquel Muñoz I Ordoño, Thomas Wiesner, Johannes Zuber, Göran Jönsson, Jan P Böttcher, Sakari Vanharanta, Anna C Obenauf.

The tumour microenvironment is programmed by cancer cells and substantially influences anti-tumour immune responses1,2. Within the tumour microenvironment, CD8+ T cells undergo full effector differentiation and acquire cytotoxic anti-tumour functions in specialized niches3-7. Although interactions with type 1 conventional dendritic cells have been implicated in this process3-5,8-10, the underlying cellular players and molecular mechanisms remain incompletely understood. Here we show that inflammatory monocytes can adopt a pivotal role in intratumoral T cell stimulation. These cells express Cxcl9, Cxcl10 and Il15, but in contrast to type 1 conventional dendritic cells, which cross-present antigens, inflammatory monocytes obtain and present peptide-major histocompatibility complex class I complexes from tumour cells through 'cross-dressing'. Hyperactivation of MAPK signalling in cancer cells hampers this process by coordinately blunting the production of type I interferon (IFN-I) cytokines and inducing the secretion of prostaglandin E2 (PGE2), which impairs the inflammatory monocyte state and intratumoral T cell stimulation. Enhancing IFN-I cytokine production and blocking PGE2 secretion restores this process and re-sensitizes tumours to T cell-mediated immunity. Together, our work uncovers a central role of inflammatory monocytes in intratumoral T cell stimulation, elucidates how oncogenic signalling disrupts T cell responses through counter-regulation of PGE2 and IFN-I, and proposes rational combination therapies to enhance immunotherapies.

DOI: https://doi.org/10.1038/s41586-024-08257-4
Nat Commun. 2024 Nov 28. 15(1): 10342

The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk.

M Pilar Valdecantos, Laura Ruiz, Cintia Folgueira, Patricia Rada, Beatriz Gomez-Santos, Maite Solas, Ana B Hitos, Joss Field, Vera Francisco, Carmen Escalona-Garrido, Sebastián Zagmutt, María Calderon-Dominguez, Paula Mera, Irma Garcia-Martinez, Elsa Maymó-Masip, Diana Grajales, Rosa Alen, Alfonso Mora, Neira Sáinz, Irene Vides-Urrestarazu, Nuria Vilarrasa, José M Arbones-Mainar, Carlos Zaragoza, María J Moreno-Aliaga, Patricia Aspichueta, Sonia Fernández-Veledo, Joan Vendrell, Dolors Serra, Laura Herrero, Renate Schreiber, Rudolf Zechner, Guadalupe Sabio, David Hornigold, Cristina M Rondinone, Lutz Jermutus, Joseph Grimsby, Ángela M Valverde.

Bariatric surgery is effective for the treatment and remission of obesity and type 2 diabetes, but pharmacological approaches which exert similar metabolic adaptations are needed to avoid post-surgical complications. Here we show how G49, an oxyntomodulin (OXM) analog and dual glucagon/glucagon-like peptide-1 receptor (GCGR/GLP-1R) agonist, triggers an inter-organ crosstalk between adipose tissue, pancreas, and liver which is initiated by a rapid release of free fatty acids (FFAs) by white adipose tissue (WAT) in a GCGR-dependent manner. This interactome leads to elevations in adiponectin and fibroblast growth factor 21 (FGF21), causing WAT beiging, brown adipose tissue (BAT) activation, increased energy expenditure (EE) and weight loss. Elevation of OXM, under basal and postprandial conditions, and similar metabolic adaptations after G49 treatment were found in plasma from patients with obesity early after metabolic bariatric surgery. These results identify G49 as a potential pharmacological alternative sharing with bariatric surgery hormonal and metabolic pathways.

DOI: https://doi.org/10.1038/s41467-024-54080-w
Sci Rep. 2024 11 25. 14(1): 29179

Endothelial eNOS deficiency causes podocyte injury through NFAT2 and heparanase in diabetic mice.

Daisuke Katagiri, Shinya Nagasaka, Keiko Takahashi, Suwan Wang, Ambra Pozzi, Roy Zent, Akira Shimizu, Ming-Zhi Zhang, Joachim R Göthert, Toin H van Kuppevelt, Raymond C Harris, Takamune Takahashi.

  The pivotal role of endothelial nitric oxide synthase (eNOS) in diabetic nephropathy (DN) has been demonstrated using global eNOS knockout (eNOSGKO) mice. However, the precise role of endothelially expressed eNOS and how its deficiency advances DN are still unclear. Here, we targeted endothelial eNOS expression (E-eNOSKO) after the onset of diabetes using the floxed eNOS and endSCL-CreERT alleles. Diabetes was induced by low-dose streptozotocin injections. To evaluate the role of nuclear factor of activated T cells-2 (NFAT2) in podocyte injury in this condition, podocyte-specific NFAT2KO mice were also generated on eNOSGKO mice. The mechanisms of podocyte injury were investigated using cultured podocytes. Compared with diabetic wild-type mice, diabetic E-eNOSKO mice showed more advanced DN accompanied by NFAT2 expression in podocytes. NO donor suppressed NFAT2 expression and activation in high-glucose cultured podocytes as well as in diabetic E-eNOSKO mice. Furthermore, podocyte-specific deletion of NFAT2 attenuated DN in diabetic eNOSGKO mice accompanied by decreased heparanase (HPSE) expression in podocytes. Consistent with this finding, HPSE was upregulated by NFAT2 transfection and suppressed by NFAT2 siRNA or NO donor treatment in cultured podocytes. HPSE transfection reduced podocyte attachment to extracellular matrix concurrent with syndecan-4 (SDC4) shedding, and this effect was attenuated by co-transfection of SDC4. Finally, HPSE inhibitor treatment attenuated podocyte injury in diabetic E-eNOSKO mice with increased SDC4 expression in podocytes. Collectively, our data suggest that endothelial eNOS deficiency causes podocyte HPSE expression in diabetic mice through NFAT2, and HPSE promotes podocyte detachment in part through SDC4 shedding, advancing DN.

Keywords:  Diabetic nephropathy; Heparanase; NFAT2; Podocyte; eNOS

DOI:  https://doi.org/10.1038/s41598-024-79501-0
Nat Cardiovasc Res. 2024 Nov 27.

Mouse and human macrophages and their roles in cardiovascular health and disease.

Alexandre Gallerand, Jichang Han, Stoyan Ivanov, Gwendalyn J Randolph.

The past 15 years have witnessed a leap in understanding the life cycle, gene expression profiles, origins and functions of mouse macrophages in many tissues, including macrophages of the artery wall and heart that have critical roles in cardiovascular health. Here, we review the phenotypical and functional diversity of macrophage populations in multiple organs and discuss the roles that proliferation, survival, and recruitment and replenishment from monocytes have in maintaining macrophages in homeostasis and inflammatory states such as atherosclerosis and myocardial infarction. We also introduce emerging data that better characterize the life cycle and phenotypic profiles of human macrophages. We discuss the similarities and differences between murine and human macrophages, raising the possibility that tissue-resident macrophages in humans may rely more on bone marrow-derived monocytes than in mouse.

DOI: https://doi.org/10.1038/s44161-024-00580-3
Sci Transl Med. 2024 Nov 27. 16(775): eadl1666

Childhood-onset lupus nephritis is characterized by complex interactions between kidney stroma and infiltrating immune cells.

Patrick Danaher, Nicholas Hasle, Elizabeth D Nguyen, Jordan E Roberts, Natalie Rosenwasser, Christian Rickert, Elena W Y Hsieh, Kristen Hayward, Daryl M Okamura, Charles E Alpers, Robyn C Reed, Sarah K Baxter, Shaun W Jackson.

Children with systemic lupus erythematosus (SLE) are at increased risk of developing kidney disease, termed childhood-onset lupus nephritis (cLN). Single-cell transcriptomics of dissociated kidney tissue has advanced our understanding of LN pathogenesis, but loss of spatial resolution prevents interrogation of in situ cellular interactions. Using a technical advance in spatial transcriptomics, we generated a spatially resolved, single-cell resolution atlas of kidney tissue from eight patients with cLN and four control individuals. Annotated cells were assigned to 30 reference cell types, including major kidney subsets and infiltrating immune cells. Analysis of spatial distribution demonstrated that individual immune lineages localized to specific regions in cLN kidneys, including myeloid cells that trafficked to inflamed glomeruli and B cells that clustered within tubulointerstitial immune hotspots. Gene expression varied as a function of tissue location, demonstrating how incorporation of spatial data can provide new insights into the immunopathogenesis of SLE. Alterations in immune phenotypes were accompanied by parallel changes in gene expression by resident kidney stromal cells. However, there was little correlation between histologic scoring of cLN disease activity and glomerular cell transcriptional signatures at the level of individual glomeruli. Last, we identified modules of spatially correlated gene expression with predicted roles in induction of inflammation and the development of tubulointerstitial fibrosis. Single-cell spatial transcriptomics allowed insights into the molecular heterogeneity of cLN, paving the way toward more targeted and personalized treatment approaches.

DOI: https://doi.org/10.1126/scitranslmed.adl1666
Proc Natl Acad Sci U S A. 2024 Dec 03. 121(49): e2416882121

PGC-1α drives small cell neuroendocrine cancer progression toward an ASCL1-expressing subtype with increased mitochondrial capacity.

Grigor Varuzhanyan, Chia-Chun Chen, Jack Freeland, Tian He, Wendy Tran, Kai Song, Liang Wang, Donghui Cheng, Shili Xu, Gabriella A Dibernardo, Favour N Esedebe, Vipul Bhatia, Mingqi Han, Evan R Abt, Jung Wook Park, Sanaz Memarzadeh, David B Shackelford, John K Lee, Thomas G Graeber, Orian S Shirihai, Owen N Witte.

  Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers composed of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands of patient tumors and human cancer cell lines uncovered enhanced expression of proliferator-activatedreceptor gamma coactivator 1-alpha (PGC-1α), a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), across several SCNCs. PGC-1α correlated tightly with increased expression of the lineage marker Achaete-scute homolog 1, (ASCL1) through a positive feedback mechanism. Analyses using a human prostate tissue-based SCN transformation system showed that the ASCL1 subtype has heightened PGC-1α expression and OXPHOS activity. PGC-1α inhibition diminished OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. Conversely, PGC-1α overexpression enhanced OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled the SCN prostate tumor formation rate, and promoted commitment to the ASCL1 lineage. These results establish PGC-1α as a driver of SCNC progression and subtype determination, highlighting metabolic vulnerabilities in SCNCs across different tissues.

Keywords:  ASCL1; PGC-1a; lung cancer; oxidative phosphorylation; prostate cancer

DOI:  https://doi.org/10.1073/pnas.2416882121
Cell Rep Methods. 2024 Nov 20. pii: S2667-2375(24)00299-6. [Epub ahead of print] 100909

Patient-derived tumor organoid and fibroblast assembloid models for interrogation of the tumor microenvironment in esophageal adenocarcinoma.

Benjamin P Sharpe, Liliya A Nazlamova, Carmen Tse, David A Johnston, Jaya Thomas, Rhianna Blyth, Oliver J Pickering, Ben Grace, Jack Harrington, Rushda Rajak, Matthew Rose-Zerilli, Zoe S Walters, Tim J Underwood.

  The tumor microenvironment (TME) comprises all non-tumor elements of cancer and strongly influences disease progression and phenotype. To understand tumor biology and accurately test new therapeutic strategies, representative models should contain both tumor cells and normal cells of the TME. Here, we describe and characterize co-culture tumor-derived organoids and cancer-associated fibroblasts (CAFs), a major component of the TME, in matrix-embedded assembloid models of esophageal adenocarcinoma (EAC). We demonstrate that the assembloid models faithfully recapitulate the differentiation status of EAC and different CAF phenotypes found in the EAC patient TME. We evaluate cell phenotypes by combining tissue-clearing techniques with whole-mount immunofluorescence and histology, providing a practical framework for the characterization of cancer assembloids.

Keywords:  CP: Cancer biology; CP: Stem cell; assembloids; cancer-associated fibroblasts; esophageal adenocarcinoma; organoids; tumor microenvironment

DOI:  https://doi.org/10.1016/j.crmeth.2024.100909
Cell Rep Med. 2024 Nov 19. pii: S2666-3791(24)00601-3. [Epub ahead of print] 101830

Macrophages are activated toward phagocytic lymphoma cell clearance by pentose phosphate pathway inhibition.

Anna C Beielstein, Elena Izquierdo, Stuart Blakemore, Nadine Nickel, Michael Michalik, Samruddhi Chawan, Reinhild Brinker, Hans-Henrik Bartel, Daniela Vorholt, Lukas Albert, Janica L Nolte, Rebecca Linke, Carolina Raíssa Costa Picossi, Jorge Sáiz, Felix Picard, Alexandra Florin, Jörn Meinel, Reinhard Büttner, Paul Diefenhardt, Sebastian Brähler, Alma Villaseñor, Holger Winkels, Michael Hallek, Marcus Krüger, Coral Barbas, Christian P Pallasch.

  Macrophages in the B cell lymphoma microenvironment represent a functional node in progression and therapeutic response. We assessed metabolic regulation of macrophages in the context of therapeutic antibody-mediated phagocytosis. Pentose phosphate pathway (PPP) inhibition induces increased phagocytic lymphoma cell clearance by macrophages in vitro, in primary human chronic lymphocytic leukemia (CLL) patient co-cultures, and in mouse models. Addition of the PPP inhibitor S3 to antibody therapy achieves significantly prolonged overall survival in an aggressive B cell lymphoma mouse model. PPP inhibition induces metabolic activation and pro-inflammatory polarization of macrophages while it decreases macrophages' support for survival of lymphoma cells empowering anti-lymphoma function. As a mechanism of macrophage repolarization, the link between PPP and immune regulation was identified. PPP inhibition causes decreased glycogen level and subsequent modulation of the immune modulatory uridine diphosphate glucose (UDPG)-Stat1-Irg1-itaconate axis. Thus, we hypothesize the PPP as a key regulator and targetable modulator of macrophage activity in lymphoma to improve efficacy of immunotherapies and prolong survival.

Keywords:  ADCP; Irg1; immunotherapy; itaconate; lymphoma; macrophage; metabolic modulation; pentose phosphate pathway; phagocytosis; polarization

DOI:  https://doi.org/10.1016/j.xcrm.2024.101830