Redox regulation of the immune response

Cellular and Molecular Immunology, Journal Year: 2022, Volume and Issue: 19(10), P. 1079 - 1101

Published: Sept. 2, 2022

Abstract The immune-inflammatory response is associated with increased nitro-oxidative stress. aim of this mechanistic review to examine: (a) the role redox-sensitive transcription factors and enzymes, ROS/RNS production, activity cellular antioxidants in activation performance macrophages, dendritic cells, neutrophils, T-cells, B-cells, natural killer cells; (b) involvement high-density lipoprotein (HDL), apolipoprotein A1 (ApoA1), paraoxonase-1 (PON1), oxidized phospholipids regulating immune response; (c) detrimental effects hypernitrosylation chronic stress on response. redox changes during responses are orchestrated by actions nuclear factor-κB, HIF1α, target rapamycin, phosphatidylinositol 3-kinase/protein kinase B signaling pathway, mitogen-activated protein kinases, 5' AMP-activated kinase, peroxisome proliferator-activated receptor. survival individual cells under control depends intracellular extracellular levels ROS/RNS. They heavily influenced including glutathione thioredoxin systems, factor erythroid 2-related 2, HDL/ApoA1/PON1 complex. Chronic inhibit those antioxidant tricarboxylic acid cycle, mitochondrial functions, metabolism cells. In conclusion, redox-associated mechanisms modulate metabolic reprogramming macrophage T helper cell polarization, phagocytosis, production pro- versus anti-inflammatory cytokines, training tolerance, chemotaxis, pathogen sensing, antiviral antibacterial effects, Toll-like receptor activity, endotoxin tolerance.

Language: Английский

---

Amino Acid Depletion Therapies: Starving Cancer Cells to Death

Trends in Endocrinology and Metabolism, Journal Year: 2021, Volume and Issue: 32(6), P. 367 - 381

Published: March 29, 2021

Targeting tumor cell metabolism is an attractive form of therapy, as it may enhance treatment response in therapy resistant cancers well mitigate treatment-related toxicities by reducing the need for genotoxic agents. To meet their increased demand biomass accumulation and energy production to maintain redox homeostasis, cells undergo profound changes metabolism. In addition diversion glucose metabolism, this achieved upregulation amino acid Interfering with availability can be selectively lethal has proven a cancer specific Achilles' heel. Here we review biology behind such dependencies discuss how these vulnerabilities exploited improve therapies.

Language: Английский

---

Arginine Signaling and Cancer Metabolism

Cancers, Journal Year: 2021, Volume and Issue: 13(14), P. 3541 - 3541

Published: July 15, 2021

Arginine is an amino acid critically involved in multiple cellular processes including the syntheses of nitric oxide and polyamines, a direct activator mTOR, nutrient-sensing kinase strongly implicated carcinogenesis. Yet, it also considered as non- or semi-essential acid, due to normal cells’ intrinsic ability synthesize arginine from citrulline aspartate via ASS1 (argininosuccinate synthase 1) ASL lyase). As such, can be used dietary supplement its depletion therapeutic strategy. Strikingly, over 70% tumors, transcription suppressed, rendering cells addicted external arginine, forming basis arginine-deprivation therapy. In this review, we will discuss signaling metabolite, arginine’s role cancer metabolism, epigenetic regulator, immunomodulator, target. We provide comprehensive summary ADI (arginine deiminase)-based preclinical studies update clinical trials for arginase. The different cell killing mechanisms associated with various types described.

Language: Английский

---

Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy

Cancers, Journal Year: 2021, Volume and Issue: 13(5), P. 986 - 986

Published: Feb. 27, 2021

It has been well-established that cancer cells are under constant oxidative stress, as reflected by elevated basal level of reactive oxygen species (ROS), due to increased metabolism driven aberrant cell growth. Cancer can adapt maintain redox homeostasis through a variety mechanisms. The prevalent perception about ROS is they one the key drivers promoting tumor initiation, progression, metastasis, and drug resistance. Based on this notion, numerous antioxidants aim mitigate stress have tested for prevention or treatment, although effectiveness strategy yet be established. In recent years, it increasingly appreciated complex, multifaceted role in microenvironment (TME), targeted amplify inside cause destruction. Accumulating evidence indicates immunotherapies alter intensify resulting ROS-dependent rejection. Herein we review progresses regarding impact various immune TME, discuss emerging ROS-modulating strategies used combination with achieve enhanced antitumor effects.

Language: Английский

---

Tissue-resident memory T cells in tumor immunity and immunotherapy

The Journal of Experimental Medicine, Journal Year: 2021, Volume and Issue: 218(4)

Published: March 23, 2021

Tissue-resident memory T cells (TRM) represent a heterogeneous cell population with the functionality of both effector and cells. TRM express residence gene signatures. This feature allows them to traffic to, reside in, potentially patrol peripheral tissues, thereby enforcing an efficient long-term immune-protective role. Recent studies have revealed involvement in tumor immune responses. infiltration correlates enhanced response current immunotherapy is often associated favorable clinical outcome patients cancer. Thus, targeting may lead cancer efficacy. Here, we review discuss recent advances on nature context immunity immunotherapy.

Language: Английский

---

SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity

Nature, Journal Year: 2023, Volume and Issue: 620(7972), P. 200 - 208

Published: July 5, 2023

Abstract Cancer cells evade T cell-mediated killing through tumour–immune interactions whose mechanisms are not well understood 1,2 . Dendritic (DCs), especially type-1 conventional DCs (cDC1s), mediate cell priming and therapeutic efficacy against tumours 3 DC functions orchestrated by pattern recognition receptors 3–5 , although other signals involved remain incompletely defined. Nutrients emerging mediators of adaptive immunity 6–8 but whether nutrients affect function or communication between innate immune is largely unresolved. Here we establish glutamine as an intercellular metabolic checkpoint that dictates tumour–cDC1 crosstalk licenses cDC1 in activating cytotoxic cells. Intratumoral supplementation inhibits tumour growth augmenting cDC1-mediated CD8 + immunity, overcomes resistance to blockade immunotherapies. Mechanistically, cDC1s compete for uptake via the transporter SLC38A2 tune anti-tumour immunity. Nutrient screening integrative analyses show dominant amino acid promoting function. Further, signalling FLCN impinges on TFEB Loss selectively impairs vivo a TFEB-dependent manner phenocopies deficiency eliminating effect supplementation. Our findings glutamine-mediated underpins evasion, reveal acquisition limiting events activation putative targets cancer treatment.

Language: Английский

---

Cancer metabolism and tumor microenvironment: fostering each other?

Science China Life Sciences, Journal Year: 2021, Volume and Issue: 65(2), P. 236 - 279

Published: Nov. 26, 2021

Language: Английский

---

Lysine catabolism reprograms tumour immunity through histone crotonylation

Nature, Journal Year: 2023, Volume and Issue: 617(7962), P. 818 - 826

Published: May 17, 2023

Language: Английский

---

Tumour-associated neutrophils secrete AGR2 to promote colorectal cancer metastasis via its receptor CD98hc–xCT

Gut, Journal Year: 2022, Volume and Issue: 71(12), P. 2489 - 2501

Published: Jan. 27, 2022

Reciprocal cellular crosstalk within the tumour microenvironment (TME) actively participates in progression. The anterior gradient-2 (AGR2) can be secreted to extracellular compartments and contribute colorectal cancer (CRC) metastasis. We investigated source for AGR2 TME underlying mechanisms mediating AGR2's effects.Tissue microarray, tissues, blood samples tumour-associated neutrophils (TANs) from patients with CRC were isolated phenotypical functional analyses. role of TAN-secreted was determined neutrophil-specific Agr2 knockout (Agr2f/f;Mrp-Cre) mice. biological roles metastasis vitro vivo.TANs a predominant cell type secreting CRC. TANs-secreted promoted cells' migration. Neutrophils-specific ablation mice ameliorated liver metastases. heavy chain CD98 (CD98hc) served as receptor AGR2. Mechanistically, increased xCT activity CD98hc-dependent manner, subsequently activating Ras homologue family member A/Rho-associated protein kinase 2 cascade. cells recruited TANs through C-X-C motif chemokine 2. Moreover, CRC-derived transforming growth factor beta 1 (TGF-β1) educated peripheral become AGR2+ that secrete Abundant infiltration high expression TGF-β1 CD98hc-xCT correlated poor prognosis CRC.Our study unveils novel between involving AGR2-CD98hc-xCT axis promotes impacts outcomes

Language: Английский

---

Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness

Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(2), P. 314 - 330

Published: Jan. 30, 2023

The accumulation of acidic metabolic waste products within the tumor microenvironment inhibits effector functions tumor-infiltrating lymphocytes (TILs). However, it remains unclear how an environment affects T cell metabolism and differentiation. Here we show that prolonged exposure to acid reprograms intracellular mitochondrial fitness preserves stemness. Mechanistically, elevated extracellular acidosis impairs methionine uptake via downregulation SLC7A5, therefore altering H3K27me3 deposition at promoters key stemness genes. These changes promote maintenance a 'stem-like memory' state improve long-term in vivo persistence anti-tumor efficacy mice. Our findings not only reveal unexpected capacity maintain stem-like properties cells, but also advance our understanding

Language: Английский

---