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Article ; Online: Dendritic Cell Metabolism and Function in Tumors.

Giovanelli, Paolo / Sandoval, Tito A / Cubillos-Ruiz, Juan R

2019 Volume 40, Issue 8, Page(s) 699–718

Abstract: Dendritic cells (DCs) are fundamental for the initiation and maintenance of immune responses against malignant cells. Despite the unique potential of DCs to elicit robust anticancer immunity, the tumor microenvironment poses a variety of challenges that ... ...

Abstract	Dendritic cells (DCs) are fundamental for the initiation and maintenance of immune responses against malignant cells. Despite the unique potential of DCs to elicit robust anticancer immunity, the tumor microenvironment poses a variety of challenges that hinder competent DC function and consequently inhibit the development of protective immune responses. Here, we discuss recent studies uncovering new molecular pathways and metabolic programs that tumors manipulate in DCs to disturb their homeostasis and evade immune control. We also examine certain state-of-the-art strategies that seek to improve DC function and elicit antitumor responses in hosts with cancer. Understanding and modulating DC metabolism and activity within tumors might help improve the efficacy of T cell-centric immunotherapies.
MeSH term(s)	Amino Acids/metabolism ; Animals ; Cellular Reprogramming ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Disease Susceptibility/immunology ; Energy Metabolism ; Glycolysis ; Humans ; Immunomodulation ; Lipid Metabolism ; Mice ; Neoplasms/etiology ; Neoplasms/metabolism ; Neoplasms/pathology ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Oxidative Stress ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; Tumor Microenvironment/immunology
Chemical Substances	Amino Acids ; Nitric Oxide (31C4KY9ESH) ; Nitric Oxide Synthase Type II (EC 1.14.13.39)
Language	English
Publishing date	2019-07-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	2036831-8
ISSN	1471-4981 ; 1471-4906
ISSN (online)	1471-4981
ISSN	1471-4906
DOI	10.1016/j.it.2019.06.004
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Zs.MG 2: Show issues

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Article ; Online: Remodeling of the Enterococcal Cell Envelope during Surface Penetration Promotes Intrinsic Resistance to Stress.

Ramos, Yusibeska / Sansone, Stephanie / Hwang, Sung-Min / Sandoval, Tito A / Zhu, Mengmeng / Zhang, Guoan / Cubillos-Ruiz, Juan R / Morales, Diana K

mBio

2022 Volume 13, Issue 6, Page(s) e0229422

Abstract: Enterococcus faecalis is a normal commensal of the human gastrointestinal tract (GIT). However, upon disruption of gut homeostasis, this nonmotile bacterium can egress from its natural niche and spread to distal organs. While this translocation process ... ...

Abstract	Enterococcus faecalis is a normal commensal of the human gastrointestinal tract (GIT). However, upon disruption of gut homeostasis, this nonmotile bacterium can egress from its natural niche and spread to distal organs. While this translocation process can lead to life-threatening systemic infections, the underlying mechanisms remain largely unexplored. Our prior work showed that E. faecalis migration across diverse surfaces requires the formation of matrix-covered multicellular aggregates and the synthesis of exopolysaccharides, but how enterococcal cells are reprogrammed during this process is unknown. Whether surface penetration endows E. faecalis with adaptive advantages is also uncertain. Here, we report that surface penetration promotes the generation of a metabolically and phenotypically distinct E. faecalis population with an enhanced capacity to endure various forms of extracellular stress. Surface-invading enterococci demonstrated major ultrastructural alterations in their cell envelope characterized by increased membrane glycolipid content. These changes were accompanied by marked induction of specific transcriptional programs enhancing cell envelope biogenesis and glycolipid metabolism. Notably, the surface-invading population demonstrated superior tolerance to membrane-damaging antimicrobials, including daptomycin and β-defensins produced by epithelial cells. Genetic mutations impairing glycolipid biosynthesis sensitized E. faecalis to envelope stressors and reduced the ability of this bacterium to penetrate semisolid surfaces and translocate through human intestinal epithelial cell monolayers. Our study reveals that surface penetration induces distinct transcriptional, metabolic, and ultrastructural changes that equip E. faecalis with enhanced capacity to resist external stressors and thrive in its surrounding environment.
MeSH term(s)	Humans ; Cell Membrane/metabolism ; Daptomycin/pharmacology ; Cell Wall/metabolism ; Enterococcus faecalis/genetics ; Biofilms ; Anti-Bacterial Agents/pharmacology
Chemical Substances	Daptomycin (NWQ5N31VKK) ; Anti-Bacterial Agents
Language	English
Publishing date	2022-11-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mbio.02294-22
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Article ; Online: Innate IRE1α-XBP1 activation by viral single-stranded RNA and its influence on lung cytokine production during SARS-CoV-2 pneumonia.

Fernández, José J / Mancebo, Cristina / Garcinuño, Sonsoles / March, Gabriel / Alvarez, Yolanda / Alonso, Sara / Inglada, Luis / Blanco, Jesús / Orduña, Antonio / Montero, Olimpio / Sandoval, Tito A / Cubillos-Ruiz, Juan R / Bustamante-Munguira, Elena / Fernández, Nieves / Crespo, Mariano Sánchez

Genes and immunity

2023 Volume 25, Issue 1, Page(s) 43–54

Abstract: The utilization of host-cell machinery during SARS-CoV-2 infection can overwhelm the protein-folding capacity of the endoplasmic reticulum and activate the unfolded protein response (UPR). The IRE1α-XBP1 arm of the UPR could also be activated by viral ... ...

Abstract	The utilization of host-cell machinery during SARS-CoV-2 infection can overwhelm the protein-folding capacity of the endoplasmic reticulum and activate the unfolded protein response (UPR). The IRE1α-XBP1 arm of the UPR could also be activated by viral RNA via Toll-like receptors. Based on these premises, a study to gain insight into the pathogenesis of COVID-19 disease was conducted using nasopharyngeal exudates and bronchioloalveolar aspirates. The presence of the mRNA of spliced XBP1 and a high expression of cytokine mRNAs were observed during active infection. TLR8 mRNA showed an overwhelming expression in comparison with TLR7 mRNA in bronchioloalveolar aspirates of COVID-19 patients, thus suggesting the presence of monocytes and monocyte-derived dendritic cells (MDDCs). In vitro experiments in MDDCs activated with ssRNA40, a synthetic mimic of SARS-CoV-2 RNA, showed induction of XBP1 splicing and the expression of proinflammatory cytokines. These responses were blunted by the IRE1α inhibitor MKC8866, the TLR8 antagonist CU-CPT9a, and knockdown of TLR8 receptor. In contrast, the IRE1α-XBP1 activator IXA4 enhanced these responses. Based on these findings, the TLR8/IRE1α system seems to play a significant role in the induction of the proinflammatory cytokines associated with severe COVID-19 disease and might be a druggable target to control cytokine storm.
MeSH term(s)	Humans ; COVID-19 ; Cytokines ; Endoribonucleases/genetics ; Endoribonucleases/metabolism ; Lung/metabolism ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; RNA, Messenger/genetics ; RNA, Viral ; SARS-CoV-2/genetics ; Toll-Like Receptor 8/genetics ; X-Box Binding Protein 1/genetics ; X-Box Binding Protein 1/metabolism
Chemical Substances	Cytokines ; Endoribonucleases (EC 3.1.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; RNA, Messenger ; RNA, Viral ; Toll-Like Receptor 8 ; X-Box Binding Protein 1 ; XBP1 protein, human ; ERN1 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2023-12-25
Publishing country	England
Document type	Journal Article
ZDB-ID	2060566-3
ISSN	1476-5470 ; 1466-4879
ISSN (online)	1476-5470
ISSN	1466-4879
DOI	10.1038/s41435-023-00243-6
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Article: Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve checkpoint blockade.

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

Research square

2023

Abstract: ... ...

Abstract	TCF1
Language	English
Publishing date	2023-09-21
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3356477/v1
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Article ; Online: Fungal Patterns Induce Cytokine Expression through Fluxes of Metabolic Intermediates That Support Glycolysis and Oxidative Phosphorylation.

Mancebo, Cristina / Fernández, José Javier / Herrero-Sánchez, Carmen / Alvarez, Yolanda / Alonso, Sara / Sandoval, Tito A / Cubillos-Ruiz, Juan R / Montero, Olimpio / Fernández, Nieves / Crespo, Mariano Sánchez

Journal of immunology (Baltimore, Md. : 1950)

2022 Volume 208, Issue 12, Page(s) 2779–2794

Abstract: Cytokine expression is fine-tuned by metabolic intermediates, which makes research on immunometabolism suitable to yield drugs with a wider prospect of application than the biological therapies that block proinflammatory cytokines. Switch from oxidative ... ...

Abstract	Cytokine expression is fine-tuned by metabolic intermediates, which makes research on immunometabolism suitable to yield drugs with a wider prospect of application than the biological therapies that block proinflammatory cytokines. Switch from oxidative phosphorylation (OXPHOS) to glycolysis has been considered a characteristic feature of activated immune cells. However, some stimuli might enhance both routes concomitantly. The connection between the tricarboxylic acid cycle and cytokine expression was scrutinized in human monocyte-derived dendritic cells stimulated with the fungal surrogate zymosan. Results showed that nucleocytosolic citrate and ATP-citrate lyase activity drove
MeSH term(s)	Citrates ; Cytokines/metabolism ; Glycolysis ; Humans ; Interleukin-10/metabolism ; NAD/metabolism ; Oxidative Phosphorylation ; Succinate Dehydrogenase/metabolism ; Succinates
Chemical Substances	Citrates ; Cytokines ; Succinates ; NAD (0U46U6E8UK) ; Interleukin-10 (130068-27-8) ; Succinate Dehydrogenase (EC 1.3.99.1)
Language	English
Publishing date	2022-06-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2100666
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Article ; Online: Evaluation of chemotherapy and P2Et extract combination in ex-vivo derived tumor mammospheres from breast cancer patients.

Urueña, Claudia / Sandoval, Tito A / Lasso, Paola / Tawil, Mauricio / Barreto, Alfonso / Torregrosa, Lilian / Fiorentino, Susana

Scientific reports

2020 Volume 10, Issue 1, Page(s) 19639

Abstract: The main cause of death by cancer is metastasis rather than local complications of primary tumors. Recent studies suggest that breast cancer stem cells (BCSCs), retains the ability to self-renew and differentiate to repopulate the entire tumor, also, ... ...

Abstract	The main cause of death by cancer is metastasis rather than local complications of primary tumors. Recent studies suggest that breast cancer stem cells (BCSCs), retains the ability to self-renew and differentiate to repopulate the entire tumor, also, they have been associated with resistance to chemotherapy and tumor recurrence, even after tumor resection. Chemotherapy has been implicated in the induction of resistant phenotypes with highly metastatic potential. Naturally occurring compounds, especially phytochemicals such as P2Et, can target different populations of cancer cells as well as BCSC, favoring the activation of immune response via immunogenic tumor death. Here, we evaluated the presence of BCSC as well as markers related to drug resistance in tumors obtained from 78 patients who had received (or not) chemotherapy before surgery. We evaluated the ex vivo response of patient tumor-derived organoids (or mammospheres) to chemotherapy alone or in combination with P2Et. A xenotransplant model engrafted with MDA-MB-468 was used to evaluate in vivo the activity of P2Et, in this model P2Et delay tumor growth. We show that patients with luminal and TNBC, and those who received neoadjuvant therapy before surgery have a higher frequency of BCSC. Further, the treatment with P2Et in mammospheres and human breast cancer cell lines improve the in vitro tumor death and decrease its viability and proliferation together with the release of immunogenic signals. P2Et could be a good co-adjuvant in antitumor therapy in patients, retarding the tumor growth by enabling the activation of the immune response.
MeSH term(s)	Adult ; Aged ; Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Caesalpinia/chemistry ; Cell Line, Tumor ; Drug Resistance, Neoplasm/drug effects ; Female ; Humans ; Mice, Inbred NOD ; Middle Aged ; Neoadjuvant Therapy/methods ; Neoplasm Recurrence, Local/drug therapy ; Neoplasm Recurrence, Local/metabolism ; Neoplasm Recurrence, Local/pathology ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Phytochemicals/pharmacology ; Plant Extracts/pharmacology ; Xenograft Model Antitumor Assays
Chemical Substances	Phytochemicals ; Plant Extracts
Language	English
Publishing date	2020-11-12
Publishing country	England
Document type	Evaluation Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-76619-9
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Article: The Microbiomes of Seven Lichen Genera Reveal Host Specificity, a Reduced Core Community and Potential as Source of Antimicrobials.

Sierra, Maria A / Danko, David C / Sandoval, Tito A / Pishchany, Gleb / Moncada, Bibiana / Kolter, Roberto / Mason, Christopher E / Zambrano, Maria Mercedes

Frontiers in microbiology

2020 Volume 11, Page(s) 398

Abstract: The High Andean Paramo ecosystem is a unique neotropical mountain biome considered a diversity and evolutionary hotspot. Lichens, which are complex symbiotic structures that contain diverse commensal microbial communities, are prevalent in Paramos. There ...

Abstract	The High Andean Paramo ecosystem is a unique neotropical mountain biome considered a diversity and evolutionary hotspot. Lichens, which are complex symbiotic structures that contain diverse commensal microbial communities, are prevalent in Paramos. There they play vital roles in soil formation and mineral fixation. In this study we analyzed the microbiomes of seven lichen genera in Colombian Paramos using 16S rRNA gene amplicon sequencing and provide the first description of the bacterial communities associated with
Language	English
Publishing date	2020-03-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587354-4
ISSN	1664-302X
ISSN	1664-302X
DOI	10.3389/fmicb.2020.00398
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Article: Transgelin 2 guards T cell lipid metabolic programming and anti-tumor function.

Research square

2023

Abstract: Mounting effective immunity against pathogens and tumors relies on the successful metabolic programming of T cells by extracellular fatty ... ...

Abstract	Mounting effective immunity against pathogens and tumors relies on the successful metabolic programming of T cells by extracellular fatty acids
Language	English
Publishing date	2023-12-14
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3683989/v1
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Article ; Online: Inflammatory ER stress responses dictate the immunopathogenic progression of systemic candidiasis.

Awasthi, Deepika / Chopra, Sahil / Cho, Byuri A / Emmanuelli, Alexander / Sandoval, Tito A / Hwang, Sung-Min / Chae, Chang-Suk / Salvagno, Camilla / Tan, Chen / Vasquez-Urbina, Liliana / Fernandez Rodriguez, Jose J / Santagostino, Sara F / Iwawaki, Takao / Romero-Sandoval, E Alfonso / Crespo, Mariano Sanchez / Morales, Diana K / Iliev, Iliyan D / Hohl, Tobias M / Cubillos-Ruiz, Juan R

The Journal of clinical investigation

2023 Volume 133, Issue 17

Abstract: Recognition of pathogen-associated molecular patterns can trigger the inositol-requiring enzyme 1 α (IRE1α) arm of the endoplasmic reticulum (ER) stress response in innate immune cells. This process maintains ER homeostasis and also coordinates diverse ... ...

Abstract	Recognition of pathogen-associated molecular patterns can trigger the inositol-requiring enzyme 1 α (IRE1α) arm of the endoplasmic reticulum (ER) stress response in innate immune cells. This process maintains ER homeostasis and also coordinates diverse immunomodulatory programs during bacterial and viral infections. However, the role of innate IRE1α signaling in response to fungal pathogens remains elusive. Here, we report that systemic infection with the human opportunistic fungal pathogen Candida albicans induced proinflammatory IRE1α hyperactivation in myeloid cells that led to fatal kidney immunopathology. Mechanistically, simultaneous activation of the TLR/IL-1R adaptor protein MyD88 and the C-type lectin receptor dectin-1 by C. albicans induced NADPH oxidase-driven generation of ROS, which caused ER stress and IRE1α-dependent overexpression of key inflammatory mediators such as IL-1β, IL-6, chemokine (C-C motif) ligand 5 (CCL5), prostaglandin E2 (PGE2), and TNF-α. Selective ablation of IRE1α in leukocytes, or treatment with an IRE1α pharmacological inhibitor, mitigated kidney inflammation and prolonged the survival of mice with systemic C. albicans infection. Therefore, controlling IRE1α hyperactivation may be useful for impeding the immunopathogenic progression of disseminated candidiasis.
MeSH term(s)	Humans ; Animals ; Mice ; Protein Serine-Threonine Kinases/metabolism ; Endoribonucleases/metabolism ; Candidiasis ; Endoplasmic Reticulum Stress ; Candida albicans ; Toll-Like Receptors/metabolism ; Adaptor Proteins, Signal Transducing/metabolism
Chemical Substances	Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Endoribonucleases (EC 3.1.-) ; Toll-Like Receptors ; Adaptor Proteins, Signal Transducing
Language	English
Publishing date	2023-09-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI167359
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Article ; Online: Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer.

Crowley, Michael J P / Bhinder, Bhavneet / Markowitz, Geoffrey J / Martin, Mitchell / Verma, Akanksha / Sandoval, Tito A / Chae, Chang-Suk / Yomtoubian, Shira / Hu, Yang / Chopra, Sahil / Tavarez, Diamile A / Giovanelli, Paolo / Gao, Dingcheng / McGraw, Timothy E / Altorki, Nasser K / Elemento, Olivier / Cubillos-Ruiz, Juan R / Mittal, Vivek

Nature communications

2023 Volume 14, Issue 1, Page(s) 120

Abstract: IRE1α-XBP1 signaling is emerging as a central orchestrator of malignant progression and immunosuppression in various cancer types. Employing a computational XBP1s detection method applied to TCGA datasets, we demonstrate that expression of the XBP1s mRNA ...

Abstract	IRE1α-XBP1 signaling is emerging as a central orchestrator of malignant progression and immunosuppression in various cancer types. Employing a computational XBP1s detection method applied to TCGA datasets, we demonstrate that expression of the XBP1s mRNA isoform predicts poor survival in non-small cell lung cancer (NSCLC) patients. Ablation of IRE1α in malignant cells delays tumor progression and extends survival in mouse models of NSCLC. This protective effect is accompanied by alterations in intratumoral immune cell subsets eliciting durable adaptive anti-cancer immunity. Mechanistically, cancer cell-intrinsic IRE1α activation sustains mPGES-1 expression, enabling production of the immunosuppressive lipid mediator prostaglandin E
MeSH term(s)	Animals ; Humans ; Mice ; Carcinoma, Non-Small-Cell Lung/genetics ; Endoribonucleases/genetics ; Endoribonucleases/metabolism ; Lung Neoplasms/genetics ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Signal Transduction ; X-Box Binding Protein 1/genetics ; X-Box Binding Protein 1/metabolism
Chemical Substances	Endoribonucleases (EC 3.1.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; X-Box Binding Protein 1 ; ERN1 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2023-01-09
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-35584-9
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