Emerging role of immunogenic cell death in cancer immunotherapy

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: May 10, 2024

Cancer immunotherapy, such as immune checkpoint blockade (ICB), has emerged a groundbreaking approach for effective cancer treatment. Despite its considerable potential, clinical studies have indicated that the current response rate to immunotherapy is suboptimal, primarily attributed low immunogenicity in certain types of malignant tumors. Immunogenic cell death (ICD) represents form regulated (RCD) capable enhancing tumor and activating tumor-specific innate adaptive responses immunocompetent hosts. Therefore, gaining deeper understanding ICD evolution crucial developing more therapeutic strategies. This review focuses exclusively on both historical recent discoveries related modes their mechanistic insights, particularly within context immunotherapy. Our findings are also highlighted, revealing mode induction facilitated by atypical interferon (IFN)-stimulated genes (ISGs), including polo-like kinase 2 ( PLK2 ), during hyperactive type I IFN signaling. The concludes discussing potential ICD, with special attention relevance preclinical settings field

Language: Английский

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Ubiquitin modification in the regulation of tumor immunotherapy resistance mechanisms and potential therapeutic targets

Experimental Hematology and Oncology, Journal Year: 2024, Volume and Issue: 13(1)

Published: Aug. 30, 2024

Abstract Although immune checkpoint-based cancer immunotherapy has shown significant efficacy in various cancers, resistance still limits its therapeutic effects. Ubiquitination modification is a mechanism that adds different types of ubiquitin chains to proteins, mediating protein degradation or altering their function, thereby affecting cellular signal transduction. Increasing evidence suggests ubiquitination plays crucial role regulating the mechanisms immunotherapy. Drugs targeting pathways have been inhibit tumor progression enhance This review elaborates on by which cells, and microenvironment mediate details how regulates these mechanisms, providing foundation for enhancing intervening modification.

Language: Английский

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In the moonlight: non-catalytic functions of ubiquitin and ubiquitin-like proteases

Frontiers in Molecular Biosciences, Journal Year: 2024, Volume and Issue: 11

Published: Feb. 22, 2024

Proteases that cleave ubiquitin or ubiquitin-like proteins (UBLs) are critical players in maintaining the homeostasis of organism. Concordantly, their dysregulation has been directly linked to various diseases, including cancer, neurodegeneration, developmental aberrations, cardiac disorders and inflammation. Given potential as novel therapeutic targets, it is essential fully understand mechanisms action. Traditionally, observed effects resulting from deficiencies deubiquitinases (DUBs) UBL proteases have often attributed misregulation substrate modification by UBLs. Therefore, much research focused on understanding catalytic activities these proteins. However, this view overlooked possibility DUBs might also significant non-catalytic functions, which more prevalent than previously believed urgently require further investigation. Moreover, multiple examples shown either selective loss only protease activity complete absence can different functional physiological consequences. Furthermore, contain domains binding motifs not modulate but mediate entirely functions. This review aims shed light non-catalytic, moonlighting functions proteases, extend beyond hydrolysis chains just beginning emerge.

Language: Английский

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Insights into CSF-1R Expression in the Tumor Microenvironment

Biomedicines, Journal Year: 2024, Volume and Issue: 12(10), P. 2381 - 2381

Published: Oct. 18, 2024

The colony-stimulating factor 1 receptor (CSF-1R) plays a pivotal role in orchestrating cellular interactions within the tumor microenvironment (TME). Although CSF-1R has been extensively studied myeloid cells, expression of this and its emerging other cell types TME need to be further analyzed. This review explores multifaceted functions across various populations, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), dendritic (DCs), cancer-associated fibroblasts (CAFs), endothelial (ECs), cancer stem (CSCs). activation by ligands, (CSF-1) Interleukin-34 (IL-34), regulates TAM polarization towards an immunosuppressive M2 phenotype, promoting progression immune evasion. Similarly, signaling influences MDSCs exert functions, hindering anti-tumor immunity. In DCs, alters antigen-presenting capabilities, compromising surveillance against cells. CAFs ECs modulation, angiogenesis, trafficking TME, fostering pro-tumorigenic milieu. Notably, CSCs contributes aggressiveness therapeutic resistance through with TAMs modulation stemness features. Understanding diverse roles underscores potential as target for treatment, aiming at disrupting crosstalk enhancing responses.

Language: Английский

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The role of type I interferon signaling in myeloid anti-tumor immunity

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 3, 2025

Tumors often arise in chronically inflamed, and thus immunologically highly active niches. While immune cells are able to recognize remove transformed cells, tumors eventually escape the control of system by shaping their immediate microenvironment. In this context, macrophages major importance, as they initially exert anti-tumor functions before adopt a tumor-associated phenotype that instead inhibits responses even allows for sustaining smoldering inflammatory, growth promoting tumor microenvironment (TME). Type I interferons (IFNs) well established modulators inflammatory reactions. have been shown directly inhibit growth, there is accumulating evidence also play an important role altering cell within TME. present review, we focus on impact type IFNs responses, driven monocytes macrophages. Specifically, will provide overview tumor-intrinsic factors, which impinge IFN-stimulated gene (ISG) expression, like presence nucleic acids, metabolites, or hypoxia. We further summarize current understanding consequences altered IFN macrophage phenotypes, i.e., differentiation, polarization, functions. For latter, macrophage-mediated killing phagocytosis, how affect environment secreting cytokines interacting with cells. Finally, discuss might should be considered future therapies.

Language: Английский

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Protease regulation of tumor-immune cell symbiosis

Trends in cancer, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

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7aaRGD - a novel SPP1/integrin signaling-blocking peptide reverses immunosuppression and improves anti-PD-1 immunotherapy outcomes in experimental gliomas

Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)

Published: April 25, 2025

Abstract Background Immune checkpoint inhibitors (ICIs) present clinical benefits in many cancer patients but invariably fail glioblastoma (GBM), the most common and deadly primary brain tumor. The lack of ICIs efficacy GBM is attributed to accumulation tumor-reprogrammed glioma-associated myeloid cells (GAMs) that create a “cold” immunosuppressive tumor microenvironment (TME), impeding infiltration activation effector T cells. GBM-derived αvβ3/αvβ5-integrin ligands, including SPP1, were shown mediate emergence GAMs. We hypothesized combination strategy aiming block reprogramming GAMs using synthetic 7aaRGD peptide targets SPP1/integrin signaling might overcome resistance reinvigorate anti-tumor immunity. Methods Matrigel invasion assay was used test glioma-microglia co-cultures. determined impact 7aaRGD, administered as monotherapy or combined with PD-1 blockade, on growth, phenotypes, arginase-1 levels neovasculature experimental gliomas. effects treatments immune landscape dissected multiparameter flow cytometry, immunocytochemistry, cytokine profiling RNA-seq analysis sorted followed by CITE-seq based data deconvolution. Results efficiently blocked microglia-dependent human mouse glioma vitro. Intratumorally delivered alone did not reduce growth orthotopic gliomas prevented led normalization peritumoral blood vessels. Combining anti-PD-1 antibody resulted reduced an increase number proliferating, interferon-ɣ producing CD8 + depletion regulatory Transcriptomic profiles altered treatment, reflecting restored “hot” inflammatory TME boosted immunotherapy responses. Intratumoral administration similarly modified phenotypes U87-MG immunocompromised mice. Exploration transcriptomic datasets revealed high expression integrin receptor coding genes pre-treatment biopsies associated poorer response check-point blockade several types cancers. Conclusions demonstrate combining modifies innate immunity reinvigorates adaptive antitumor responses, which paves way improve outcomes GBM. Graphical abstract

Language: Английский

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Parkin activates innate immunity and promotes anti-tumor immune responses

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 29, 2024

The activation of innate immunity and associated interferon (IFN) signaling have been implicated in cancer, but the regulators are elusive a link to tumor suppression undetermined. Here, we found that Parkin, an E3 ubiquitin ligase altered Parkinson's Disease was epigenetically silenced cancer its re-expression by clinically approved demethylating therapy stimulated transcription potent IFN response cells. This pathway required Parkin activity, involved subcellular trafficking release alarmin High Mobility Group Box 1 (HMGB1) with inhibition NFκB gene expression. In turn, Parkin-expressing cells released secretome upregulated effector cytotoxic CD8 T cell markers, lowered expression immune inhibitory receptors, TIM3 LAG3, high content self-renewal/stem factor, TCF1. Parkin-induced selectively accumulated microenvironment inhibited transgenic syngeneic growth, vivo. Therefore, is regulated activator dual mode suppressor, inhibiting intrinsic traits metabolism invasion, while simultaneously reinvigorating functions microenvironment.

Language: Английский

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The ISG15-Protease USP18 Is a Pleiotropic Enhancer of HIV-1 Replication

Viruses, Journal Year: 2024, Volume and Issue: 16(4), P. 485 - 485

Published: March 22, 2024

The innate immune response to viruses is formed in part by interferon (IFN)-induced restriction factors, including ISG15, p21, and SAMHD1. IFN production can be blocked the ISG15-specific protease USP18. HIV-1 has evolved circumvent host surveillance. This mechanism might involve In our recent studies, we demonstrate that infection induces USP18, which dramatically enhances replication abrogating antiviral function of p21. USP18 downregulates p21 accumulating misfolded dominant negative p53, inactivates wild-type p53 transactivation, leading upregulation key enzymes involved de novo dNTP biosynthesis pathways inactivated Despite USP18-mediated increase DNA infected cells, it intriguing note cGAS-STING-mediated sensing viral abrogated. Indeed, expression or knockout ISG15 inhibits HIV-1. We STING ISGylated at residues K224, K236, K289, K347, K338, K370. inhibition K289-linked ISGylation suppresses its oligomerization induction. propose human a novel factor potentially contributes multiple ways replication.

Language: Английский

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Protocol to study the immune profile of syngeneic mouse tumor models

STAR Protocols, Journal Year: 2024, Volume and Issue: 5(3), P. 103139 - 103139

Published: June 14, 2024

Protocol to study the immune profile of syngeneic mouse tumor models Flow cytometry, single-cell RNA sequencing, and other analyses enable us capture profiles microenvironment.Here, we present a protocol characterize tumor-bearing mice.We describe steps for establishing preparing suspensions from tissue immune-related organs, which can be further analyzed by flow cytometry omics assays.We then detail procedures staining, analysis, phenotyping cell populations.

Language: Английский

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