Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy

ABSTRACT: Immunotherapy is revolutionizing cancer treatment, but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions remains poorly understood. Here, using anti-CD40-treatment in mice as a model of Th1-promoting immunotherapy, we show liver macrophages’ vulnerability to promote local adverse events. Mechanistically, tissue-resident Kupffer cells mediate liver toxicity by sensing lymphocyte-derived IFN-g and producing IL-12. Conversely, dendritic cells are dispensable for toxicity but drive tumor control. Though macrophages, IL-12, and IFN-g are not necessarily toxic themselves, we find that they prompt a neutrophil response that determines the severity of tissue damage. We further show that similar inflammatory pathways characterize adverse events across tissues, following anti-PD-1 and anti-CTLA4 immunotherapies, and in humans. These findings implicate macrophages and neutrophils as mediators and effectors of aberrant inflammation in Th1-promoting immunotherapy, and suggest distinct mechanisms of toxicity and antitumor immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE176109 | GEO | 2021/06/04

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy

Project description:Immunotherapy is revolutionizing cancer treatment but can trigger toxicities that remain poorly understood. Here, by comprehensively analyzing mouse models following anti-CD40 therapy, we found an interdependent induction of the cytokines IFN-g and IL-12, which caused inflammatory pathology in various tumor-free tissues. In the liver, Kupffer cells mediated toxicity by sensing lymphocyte-derived IFN-g and producing IL-12, highlighting the vulnerability of tissue-resident macrophages to promote toxicity when reacting to proinflammatory cues. Conversely, dendritic cells drove tumor control but were dispensable for toxicity. We further show that liver macrophages, IL-12, and IFN-g were not toxic themselves, but prompted a neutrophil response that determined the severity of tissue damage. Similar inflammatory pathways characterized immunotherapy-related adverse events in cancer patients. These findings implicate resident macrophages and neutrophils as mediators and effectors of aberrant inflammation, and suggest distinct cellular mechanisms of toxicity and antitumor immunity.

2021-06-03 | GSE175737 | GEO

Single-cell transcriptomics reveals the natural product cannabinoid rewires tumor microenvironment via inhibiting alternative activation of macrophage and synergizes with PD-1 blockade

Project description:Colorectal tumors often display a suppressive immune microenvironment that limits their response to immunotherapy. Here, we report that Cannabidiol, a natural non-psychoactive constituent of the cannabis plant, inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment. Our single-cell transcriptome sequencing results showed that CBD inhibits M2-polarized macrophages while promoting M1-polarized macrophages, which restores the intrinsic antitumor properties of macrophages to inhibit tumor progression. Mechanistically, CBD inhibits alternative activation of macrophages by inhibiting PI3K-Akt signaling, which shifts cell metabolism from oxidative phosphorylation and fatty acid oxidation to glycolysis. Moreover, CBD-mediated macrophage plasticity enhanced the response to anti-PD1 immunotherapy in xenograft mice. Taken together, our study provides new insights into the antitumor effects of CBD.

2023-09-29 | GSE220635 | GEO

Inflammation driven by tumor-specific Th1 cells protects against B-cell cancer

Project description:The immune system can both promote and suppress cancer. Chronic inflammation and proinflammatory cytokines such as interleukin (IL)-1 and IL-6 are considered tumor-promoting. In contrast, the exact nature of protective antitumor immunity remains obscure. In this study, we have quantified locally secreted cytokines during primary immune responses against myeloma and B-cell lymphoma in mice. Strikingly, successful cancer immunosurveillance mediated by tumor-specific CD4+ T cells was consistently associated with elevated local levels of both proinflammatory (IL-1aplha, IL-1beta, and IL-6) and T helper 1 (Th1)-associated cytokines (interferon-alpha, IL-2, IL-12). Cancer eradication was achieved by a collaboration between tumor-specific Th1 cells and tumor-infiltrating, antigen-presenting macrophages. Th1 cells induced secretion of IL-1? and IL-6 by macrophages. Th1-derived interferon-? was shown to render macrophages directly cytotoxic to cancer cells, and to induce macrophages to secrete the angiostatic chemokines CXCL9/MIG and CXCL10/IP-10. Thus, inflammation, when driven by tumor-specific Th1 cells, may prevent rather than promote cancer. Tumoricidal macrophages were isolated from Idiotype-specific TCR-transgenic SCID mice injected with MOPC315-containing Matrigel. Control macrophages were obtained from TCR-transgenic SCID mice injected with Matrigel containing antigen-loss MOPC315.

2011-03-15 | E-GEOD-26912 | biostudies-arrayexpress

Bispecific antibodies increase the therapeutic window of CD40 agonists through selective dendritic cell targeting

Project description:Therapeutic use of agonistic anti-CD40 antibodies is a potentially powerful approach for activating the immune response to eradicate tumors. However, the translation of this approach to clinical practice has been significantly restricted due to the severe dose-limiting toxicities observed in multiple clinical trials. Here, we demonstrate that conventional type-1 dendritic cells are essential for triggering antitumor immunity but not toxicity by CD40 agonists, while macrophages, platelets, and monocytes lead to the toxic events. Therefore, we designed bispecific antibodies that target CD40 activation preferentially to dendritic cells. These bispecific reagents demonstrate a superior safety profile compared to their parental CD40 monospecific antibody, while triggering potent anti-tumor activity. We suggest such cell-selective bispecific agonistic antibodies as a drug platform to bypass the dose-limiting toxicities of anti-CD40, and of additional types of agonistic antibodies used for cancer immunotherapy.

2021-12-12 | GSE184009 | GEO

Local Delivery of mRNA Encoding Cytokines Promotes Antitumor Immunity and Tumor Eradication Across Multiple Preclinical Tumor Models

Project description:Local immunotherapy ideally stimulates immune responses against tumors while avoiding toxicities associated with systemic administration. Current strategies for tumor-targeted, gene-based delivery, however, are limited by adverse effects such as off-targeting or anti-vector immunity. We investigated the intratumoral administration of saline-formulated messenger (m)RNA encoding four cytokines that were identified as mediators of tumor regression across different tumor models: interleukin (IL)-12 single chain, interferon (IFN)-α, granulocyte-macrophage colony-stimulating factor, and IL-15 sushi. Effective antitumor activity of these cytokines relied on multiple immune cell populations and was accompanied by intratumoral IFN-γ induction, systemic antigen-specific T cell expansion, increased granzyme B+ T cell infiltration, and formation of immune memory. Antitumor activity extended beyond the treated lesions and inhibited growth of distant tumors as well as disseminated tumors. Combining the mRNAs with immunomodulatory antibodies enhanced antitumor responses in both injected and uninjected tumors, thus improving survival and tumor regression. Consequently, clinical testing of this cytokine-encoding mRNA mixture is now underway.

2021-07-10 | GSE179738 | GEO

Identification of a novel antitumor CD4+ T cell cluster orchestrating antitumor immunity

Project description:scRNAseq-based unsupervised clustering and clonotyping revealed that Th1/17 and CCR6 SP clusters formed metacluster Th7R, which was distinct from Th1 or Th17, characterized by high expression of the IL-7 receptor. Use of this cluster to assess antitumor CD4+ T cell immunity from the peripheral blood and to predict the efficacy of immune checkpoint inhibitors will pave the way for novel antitumor immunotherapy strategies for patients.

2022-12-21 | GSE168844 | GEO

Inflammation driven by tumor-specific Th1 cells protects against B-cell cancer

2011-03-15 | GSE26912 | GEO

Transcriptome analysis of Th1 cells from spleen, lymph nodes, draining lymph nodes and B16-F10 tumor

Project description:It is now clearly established that immune system can affect cancer response to therapy. However, the influence of tumor microenvironment on immune cells is not completely understood. In this respect, alternative splicing is increasingly described to affect immune system biology. Here, we showed that tumor microenvironment, by increasing alternative splicing events, induced the expression of an alternative isoform of the IRF1 transcription factor in Th1 cells. Furthermore, we also shown, in both mice and humans, that IRF1 alternative isoform alters IRF1 full form transcriptional activity on Il12rb1 promotor, resulting in decreased IFN-? secretion in Th1 cells. Thus, IRF1-short isoform increases in tumor microenvironment and to prevent this isoform appearance could potentiate Th1 cell antitumor effect.

2021-04-27 | GSE134853 | GEO

Transcriptome analysis of CD4+ T cells from spleen and MC38 tumor

2021-04-27 | GSE134851 | GEO

Beyond the polymerase-gamma theory: Respiratory chain inhibition and production of ROS as modes of NRTI induced mitochondrial toxicity

Project description:HIV-1 nucleoside reverse transcriptase inhibitor (NRTI) use is associated with severe adverse events. However, the exact mechanisms behind their toxicity has not been fully understood. Mitochondrial dysfunction after chronic exposure to NRTIs has predominantly been assigned to mitochondrial polymerase- inhibition by NRTIs. However, an increasing amount of data suggests that this is not the sole mechanism. Many NRTI induced adverse events have been linked to the incurrence of oxidative stress, although the causality of events leading to reactive oxygen species (ROS) production and their role in toxicity is unclear. In this study we show that short-term effects of these drugs, which are rarely discussed in the literature, include direct inhibition of the mitochondrial respiratory chain (MRC), decreased ATP levels and increased ROS production. Collectively these events affect fitness and longevity of C. elegans through mitohormetic signalling events. Furthermore, we demonstrate that these effects can be normalized by addition of the anti-oxidant N-acetylcysteine (NAC), which suggests that ROS likely influence the onset and severity of adverse events upon drug exposure.

2018-02-13 | GSE100482 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data