Metformin improves cancer immunotherapy by directly rescuing tumor-infiltrating CD8 T lymphocytes from hypoxia-induced immunosuppression

Journal for ImmunoTherapy of Cancer, Journal Year: 2023, Volume and Issue: 11(5), P. e005719 - e005719

Published: May 1, 2023

Background Despite their revolutionary success in cancer treatment over the last decades, immunotherapies encounter limitations certain tumor types and patients. The efficacy of depends on antigen-specific CD8 T-cell viability functionality within immunosuppressive microenvironment, where oxygen levels are often low. Hypoxia can reduce fitness several ways T cells mostly excluded from hypoxic regions. Given challenges to achieve durable reduction hypoxia clinic, ameliorating survival effector function condition could improve response immunotherapies. Methods Activated were exposed metformin analyzed by fluorescence-activated cell sorting for proliferation, apoptosis phenotype. In vivo, was administered mice bearing tumors receiving either adoptive therapy with tumor-specific cells, or immune checkpoint inhibitors; growth followed time infiltration, localization normoxic regions assessed flow cytometry immunofluorescence. Tumor oxygenation measured electron paramagnetic resonance pimonidazole staining, respectively. Results We found that antidiabetic drug directly improved hypoxia, both vitro vivo. Metformin rescued murine human hypoxia-induced increased proliferation cytokine production, while blunting upregulation programmed death protein 1 lymphocyte-activation gene 3. This appeared result a reduced production reactive species, due inhibition mitochondrial complex I. Differently what others reported, did not but rather infiltration areas, synergized cyclophosphamide enhance blockade different models. Conclusions study describes novel mechanism action presents promising strategy rejection tumors, which would otherwise be resistant immunotherapy.

Language: Английский

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Control of immune cell function by the unfolded protein response

Nature reviews. Immunology, Journal Year: 2023, Volume and Issue: 23(9), P. 546 - 562

Published: Feb. 8, 2023

Language: Английский

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The role of RNA methylation in tumor immunity and its potential in immunotherapy

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: June 20, 2024

Abstract RNA methylation, a prevalent post-transcriptional modification, has garnered considerable attention in research circles. It exerts regulatory control over diverse biological functions by modulating splicing, translation, transport, and stability. Notably, studies have illuminated the substantial impact of methylation on tumor immunity. The primary types encompass N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanosine (m7G), 3-methylcytidine (m3C). Compelling evidence underscores involvement regulating microenvironment (TME). By affecting translation stability through "writers", "erasers" "readers", influence dysregulation immune cells factors. Consequently, plays pivotal role immunity mediating various behaviors, encompassing proliferation, invasion, metastasis, etc. In this review, we discussed mechanisms several methylations, providing comprehensive overview their roles underlying within among immunocytes. exploring how these modifications mediate evasion, also examine potential applications immunotherapy. This review aims to provide novel insights strategies for identifying targets advancing cancer immunotherapy efficacy.

Language: Английский

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Histone lactylation-driven B7-H3 expression promotes tumor immune evasion

Theranostics, Journal Year: 2025, Volume and Issue: 15(6), P. 2338 - 2359

Published: Jan. 13, 2025

Rationale: Tumor cells possess sophisticated strategies to circumvent immune detection, including the modulation of endogenous checkpoints, particularly those within B7 family. Elucidating mechanisms that govern induction family molecules is crucial for advancement immunotherapy. Lysine lactylation (Kla), a newly identified epigenetic modification, suggested may play role in reshaping tumor microenvironment and facilitating evasion. Methods: We analyzed glycolysis pathway's enrichment patients with immune-evading tumors assessed impact lactate treatment on antitumor immunity CD8+ T microenvironment. interrupted using dehydrogenase A (LDHA) knockdown sodium oxamate, evaluated its effects cell cytotoxicity. Additionally, we investigated correlation between B7-H3 expression pathway, explored molecular underlying lactate-induced expression. Results: Our findings revealed pathway was highly enriched tumors. Lactate inhibited cells, whereas interruption via LDHA or oxamate augmented cytotoxicity effectively counteracting found be closely linked pathway. Mechanistically, lactate-upregulated H3K18la directly bound promoter conjunction transcription factor Creb1 co-activator Ep300, leading increased contributing progression by compromising proportion tumor-infiltrating cells. In mouse bearing models, inhibiting suppressed growth, activated demonstrated potent anti-tumor efficacy. Furthermore, this approach enhanced efficacy anti-PD-1 treatment. Conclusions: This study uncovers novel mechanism which modulates through expression, providing new avenues metabolism-targeted

Language: Английский

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Nanoenabled Disruption of Multiple Barriers in Antigen Cross-Presentation of Dendritic Cells via Calcium Interference for Enhanced Chemo-Immunotherapy

ACS Nano, Journal Year: 2020, Volume and Issue: 14(6), P. 7639 - 7650

Published: May 19, 2020

Chemo-immunotherapy holds the advantage of specific antitumor effects by activating T cell immune response. However, efficiency chemo-immunotherapy is restricted to insufficient antigen presentation dendritic cells (DCs) in tumor immunosuppression microenvironment. Here, we rationally designed a simple yet versatile calcium ion nanogenerator disrupt autophagy inhibition condition within DCs, enrich damage-associated molecular patterns (DAMPs), and attenuate acidity After chemotherapy, honeycomb carbonate (CaCO3) nanoparticles (OVA@CaCO3, denoted as HOCN, ovalbumin (OVA) acted skeleton) could preferentially accumulate display series benefits for disrupting multiple barriers cross-presentation DCs: (i) recovering viability DCs HOCN-induced attenuating; (ii) generating Ca2+ cells; (iii) improving maturation overloading-mediated enhanced DAMP release from cells. In addition, HOCN can also immunosuppressive microenvironment reducing infiltration factors. We believe regulation intratumoral offers an alternative strategy cancer chemo-immunotherapy.

Language: Английский

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Metabolism of Dendritic Cells in Tumor Microenvironment: For Immunotherapy

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: Feb. 24, 2021

Dendritic cells (DCs) are a type of an antigen-presenting cell which undertake job on capturing antigens coming from pathogens or tumors and presenting to T for immune response. The metabolism DCs controls its development, polarization, maturation processes provides energy support functions. However, the activity in tumor microenvironment (TME) is inhibited generally. Abnormal causes metabolic changes TME, such as hyperglycolysis, lactate lipid accumulation, acidification, tryptophan deprivation, limit function lead occurrence escape. Combined regulation with immunotherapy can strengthen ability antigen-presentation activation DCs, improve existing anti-tumor therapy, overcome defects DC-related therapies current stage, has great potential oncology therapy. Therefore, we reviewed glucose, lipid, amino acid well after being affected by TME. Together targets possible therapeutic pathways were summarized.

Language: Английский

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The evolving landscape of N6-methyladenosine modification in the tumor microenvironment

Molecular Therapy, Journal Year: 2021, Volume and Issue: 29(5), P. 1703 - 1715

Published: April 8, 2021

The tumor microenvironment (TME), controlled by intrinsic mechanisms of carcinogenesis and epigenetic modifications, has, in recent years, become a heavily researched topic. TME can be described terms hypoxia, metabolic dysregulation, immune escape, chronic inflammation. RNA methylation, an modification, has recently been found to have pivotal role shaping the TME. N6-methylation adenosine (m6A) modification is most common type methylation that occurs N6-position adenosine, which primary internal eukaryotic mRNA. Compelling evidence demonstrated m6A regulates transcriptional protein expression through splicing, translation, degradation, export, thereby mediating biological processes cancer cells and/or stromal characterizing also crucial complicated regulatory network modifications and, subsequently, influences initiation, progression, therapy responses. In this review, we describe features how modulates interacts with it. We focus on various factors pathways involved methylation. Finally, discuss potential therapeutic strategies prognostic biomarkers respect modification.

Language: Английский

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Hypoxia and the phenomenon of immune exclusion

Journal of Translational Medicine, Journal Year: 2021, Volume and Issue: 19(1)

Published: Jan. 6, 2021

Abstract Over the last few years, cancer immunotherapy experienced tremendous developments and it is nowadays considered a promising strategy against many types of cancer. However, exclusion lymphocytes from tumor nest common phenomenon that limits efficiency in solid tumors. Despite several mechanisms proposed during years to explain immune excluded phenotype, at present, there no integrated understanding about role played by different models human cancers. Hypoxia hallmark most tumors and, being multifaceted complex condition, shapes unique way microenvironment, affecting gene transcription chromatin remodeling. In this review, we speculate an upstream for hypoxia as biological determinant We also discuss current state ex vivo imaging hypoxic determinants relation T cell distribution could discover functional-morphological features support clinical monitoring.

Language: Английский

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Hypoxia in Solid Tumors: How Low Oxygenation Impacts the “Six Rs” of Radiotherapy

Frontiers in Endocrinology, Journal Year: 2021, Volume and Issue: 12

Published: Sept. 2, 2021

Radiotherapy is an important component of cancer treatment, with approximately 50% all patients receiving radiation therapy during their course illness. Nevertheless, solid tumors frequently exhibit hypoxic areas, which can hinder therapies efficacy, especially radiotherapy one. Indeed, hypoxia impacts the six parameters governing response, called « Rs biology » (for Radiosensitivity, Repair, Repopulation, Redistribution, Reoxygenation, and Reactivation anti-tumor immune response), by inducing pleiotropic cellular adaptions, such as cell metabolism rewiring, epigenetic landscape remodeling, death weakening, significant clinical repercussions. In this review, according to Rs, we detail how hypoxia, associated mechanisms pathways, impact response resulting implications. We finally illustrate it in endocrine cancers through a focus on anaplastic thyroid carcinomas.

Language: Английский

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Resistance to immune checkpoint inhibitors in non-small cell lung cancer: biomarkers and therapeutic strategies

Therapeutic Advances in Medical Oncology, Journal Year: 2020, Volume and Issue: 12

Published: Jan. 1, 2020

The treatment landscape for patients with advanced non-small cell lung cancer has evolved greatly the advent of immune checkpoint inhibitors. However, many do not derive benefit from blockade, developing either primary or secondary resistance, highlighting a need alternative approaches to modulate function. In this review, we highlight absence common definition and resistance summarize their frequency clinical characteristics. Furthermore, provide an overview biomarkers mechanisms involving tumor, tumor microenvironment host, suggest strategies overcome these improve outcomes.

Language: Английский

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