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Targeting TBK1 potentiates oncolytic virotherapy via RIPK1-ICAM1 mediated NK killing in chemo-resistant colorectal cancer [scRNA-seq]

ABSTRACT: Acquired chemo-resistance poses a significant challenge in cancer therapy and is a leading cause of cancer mortality. To address this issue, we explored the therapeutic potential of using oncolytic viruses (OVs) to combat chemo-resistant colorectal cancer (CRC). However, the sensitivities to different OVs, including VSVΔ51 and HSV-1, were significantly reduced in chemo-resistant CRC. Our investigation revealed that elevated TANK-binding kinase 1 (TBK1) expression in chemo-resistant CRC mediated the activation of the type I interferon pathway, which impaired viral replication and oncolysis. Inhibition of TBK1 enhanced viral replication and the antitumor efficacy of VSVΔ51 by amplifying RIPK1-mediated necroptosis both in vitro and in vivo. Analysis of immune cell profiles demonstrated that the combination treatment reshaped the tumor microenvironment and increased the influx and functional activity of natural killer (NK) cells. Immune cell depletion studies indicated that NK cells were essential for the synergistic therapeutic activity of the combination treatment. Mechanistically, TBK1 inhibitors synergized with VSVΔ51 to increase ICAM1 expression in a RIPK1-dependent manner, promoting NK cell-mediated killing. This study presents a promising approach for treating chemo-resistant CRC by combining OVs and TBK1 inhibitors.

ORGANISM(S): Mus musculus

PROVIDER: GSE293436 | GEO | 2025/06/18

REPOSITORIES: GEO

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Targeting TBK1 potentiates oncolytic virotherapy via RIPK1-ICAM1 mediated NK killing in chemo-resistant colorectal cancer [scRNA-seq]

Project description:Targeting TBK1 potentiates oncolytic virotherapy via RIPK1-ICAM1 mediated NK killing in chemo-resistant colorectal cancer [scRNA-seq]

| PRJNA1244527 | ENA

TBK1 suppresses RIPK1-driven apoptosis and inflammation during development and in aging

Project description:Aging is a major risk factor for both genetic and sporadic neurodegenerative disorders. However, it is unclear how aging interacts with genetic predispositions to promote neurodegeneration. Here we investigate how partial loss-of-function of TBK1, a major genetic cause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comorbidity, leads to age-dependent neurodegeneration. We show that TBK1 is an endogenous inhibitor of RIPK1 and the embryonic lethality of Tbk1-/- mice is dependent on RIPK1 kinase activity. In aging human brains, another endogenous RIPK1 inhibitor, TAK1, exhibits a marked decrease in expression. We show that in Tbk1+/- mice, the reduced myeloid TAK1 expression promotes all the key hallmarks of ALS/FTD, including neuroinflammation, TDP-43 aggregation, axonal degeneration, neuronal loss and behavior deficits, which are blocked upon inhibition of RIPK1. Thus, aging facilitates RIPK1 activation by reducing TAK1 expression, which cooperates with genetic risk factors to promote the onset of ALS/FTD.

2018-07-04 | GSE116613 | GEO

TBK1 and IKKε protect target cells from IFNgamma-mediated inflammatory apoptosis

Project description:T cells produce interferon gamma (IFNγ), but it is unclear whether they can use IFNγ to directly kill target cells. Here, we report that tumor targets lacking TBK1 and IKKε are killed by IFNγ, which induces expression of TNFR1 and the Z-nucleic acid sensor, ZBP1 to trigger RIPK1-dependent apoptosis. Concurrent with apoptosis, IFNγ unexpectedly also induces hyperactivation of NFκB in TBK1 and IKKε double-deficient cells. The two kinases normally function to inhibit IKKa/b activity and in their absence, IFNγ induces elevated expression of inflammatory genes. Thus, IFNγ can induce an inflammatory form of apoptosis that is normally suppressed by TBK1 and IKKε. These kinases regulate three responses: (1) induction of type I IFN; (2) inhibition of RIPK1-dependent death; and (3) inhibition of NFκB-dependent inflammation. We propose that these kinases evolved these intertwined functions so that cells infected by pathogens encoding TBK1/IKKε antagonists to block type I IFN expression will be killed by IFNγ-secreting T cells to generate an alternate NFκB-dependent inflammatory response.

2024-10-28 | GSE278131 | GEO

Non-coding RNA and mRNA expression profile in multi-drug resistance of colorectal cancer

Project description:Background: Non-coding RNAs have been proved to play an essential role in the development and progression of various cancers. However, the functions and mechanisms of non-coding RNA and mRNA in multi-drug resistance of colorectal cancer have not been fully elucidated.Methods: We performed RNA-sequencing to screen differentially expressed non-coding RNA and mRNA in CRC chemo-resistant and chemo-sensitive cell lines. Results: The results showed that 1779 mRNAs, 64 miRNAs, 11 circRNAs and 295 lncRNAs were common differentially expressed in two chemo-resistant cell lines.Conclusions:The results of the study may provide new theories and therapeutic targets for multi-drug resistance in colorectal cancer.

2024-04-28 | GSE173606 | GEO

Selection of tumor resistant variants following sustained NK-mediated immune stress

Project description:Resistance of tumor cells to cell-mediated cytotoxicity remains a drawback in the immunotherapy of cancer and its molecular basis is poorly understood. To investigate the acquisition of tumor resistance to cell-mediated cytotoxicity, resistant variants were selected following long term NK cell selection pressure. We found that these variants are resistant to NK cell-mediated lysis but still sensitive to autologous cytotoxic T lymphocytes or cytotoxic drugs. This resistance seems to be dependent, at least partly, of an alteration of the target cell recognition by NK effector cells, but does not appear to involve any alteration of KIR, DNAM1 or NKG2D ligands expression on resistant cells nor the induction of a protective autophagy. To gain further insight into the molecular mechanisms underlying the acquired tumor resistance to NK cells-mediated cytotoxicity, we have conducted a comprehensive analysis of the variants transcriptome. Comparative analysis identified an expression profile of genes that best distinguished resistant variant from parental sensitive cancer cells with candidate genes putatively involved in NK cell-mediated lysis resistance, but also in adhesion, migration and invasiveness including up-regulated genes such as POT1, L1CAM or ECM1 and down-regulated genes like B7-H6 or UCHL1. Consequently, the selected variants did not only display resistance to NK cell-mediated lysis but also exhibited more aggressive properties. The present studies emphasize that NK cells expand far beyond the simple killing of malignant cells and may be important effectors during cancer immunoediting.This study aims to compare transcriptome of T1_ref cells (2 triplicates samples untreated versus 2 triplicate samples of T1 after cocultured with NK cells).

2020-11-02 | E-MTAB-8777 | biostudies-arrayexpress

Mechanisms of caspase-8 suppression of the RIPK1-TBK1 axis in homeostatic type I interferon production and regulation

Project description:Type-I interferons (IFNs) are an essential component of the innate immune response that are upregulated in response to infection. However, a low level of basal, or tonic, IFN expression is also critical to maintain tissue homeostasis. While the regulation of type-I IFN production during infection is well studied, the mechanisms controlling this basal expression and its impacts on homeostasis remain enigmatic. Here, we report the role of caspase-8 as a negative regulator of type-I IFN production during homeostasis in vitro and in vivo. Caspase-8 deficiency led to hyperactivation of basal type-I IFN signaling across multiple cell types and tissues and provided naturally heightened resistance to viral infection with norovirus. Mechanistically, the absence of caspase-8 allowed for an interaction between RIPK1 and TBK1, leading to enhanced TBK1 activation and aberrant type-I IFN production under homeostatic conditions. Loss of RIPK1 in caspase-8–deficient cells normalized TBK1 phosphorylation, IFN production and IFN signaling, thereby sensitizing cells to viral infection-induced inflammasome activation and inflammatory cell death, PANoptosis. In vivo, the elevated type-I IFN signaling, as well as the previously established early onset lymphadenopathy at 8 weeks of age, in caspase-8–deficient mice were reduced upon deletion of RIPK1 or type-I IFN neutralization. Overall, our study identified a mechanism which constrains tonic type-I IFN production and signaling during homeostasis. These results advance our understanding of tissue homeostasis and IFN regulation in infectious, autoimmune and autoinflammatory diseases, providing new insights for the development of disease treatments.

2022-11-16 | GSE211623 | GEO

RPK1 phosphorylation and cell death

Project description:The molecular mechanisms regulating the switch between RIPK1 pro-survival and pro-death functions remain poorly understood. We identified Ikkα/β-mediated phosphorylation of RIPK1 as a key mechanism inhibiting RIPK1 kinase activity and preventing TNF-mediated RIPK1 kinase-dependent cell death.

2019-04-02 | PXD009857 | Pride

CD45+ single cell transcriptomes in the MC38 tumor microenvironment

Project description:Colorectal cancer (CRC) continues to increase globally, thus identification of mechanisms that prevent cancer are sorely needed. The microbiota has emerged as a key driver of CRC pathogenesis; however, little is known regarding how specific microbes might prevent CRC. Using transplantation of the microbiota from individuals with or without CRC into germfree mice, we identified that the microbiota harbored by non-diseased individuals can reduce tumor formation and Bacteroides uniformis was a potentially protective member of the microbiota. Single cell sequencing of CD45+ immune cells within the MC38 tumor shows a change in T and NK cell populations with B. uniformis treatment. T cell deficient mice were still protected from CRC in response to B. uniformis treatment, while NK cell depletion eradicated microbe-mediated protection. B. uniformis is reduced in individuals with CRC and thus our data identify B. uniformis as a microbe enriched in healthy individuals that can reduce tumor formation through enhanced NK cell activity.

2024-01-01 | GSE234875 | GEO

YTHDF3 improves translation initiation of mRNAs with N6-methyladenosine methylation at 5’ untranslated region by facilitating eIF2AK2 recruitment in oxaliplatin-resistant colorectal cancer

Project description:Oxaliplatin as a first-line drug frequently causes the chemo-resistance on colorectal cancer (CRC). N6-methyladenosine (m6A) methylation has been largely acknowledged in multiple biological functions. However, the molecular mechanisms underlying the m6A methylation in modulating anticancer drug resistance in CRC are still obscure. In present study, RNA-seq was conducted to investigate the transcriptome of CRC tissues from three patients at different disease stages (CapeOx combined chemotherapy sensitivity and resistance).

2022-02-05 | E-MTAB-11323 | biostudies-arrayexpress

Cxcr3 promotes protection from colorectal cancer liver metastasis by driving NK infiltration and plasticity

Project description:The anti-metastatic activity of NK cells is well established in several cancer types, but the mechanisms underlying NK cell metastasis infiltration and acquisition of anti-tumor characteristics remain unclear. Herein, we investigate the cellular and molecular factors required to facilitate the generation of an ILC1-like CD49a+NK cell population within the liver metastasis environment in orthotopic mouse models of colorectal cancer (CRC). We show that CD49a+NK cells have the highest cytotoxic capacity among metastasis-infiltrating NK cells in the MC38 mouse model. Furthermore, the chemokine receptor CXCR3 promotes CD49a+NK cell accumulation and persistence in metastasis where NK cells co-localize with macrophages in CXCL9 and CXCL10 rich areas. We confirmed the accumulation of CXCR3+ NK cells in metastatic samples mined from a published sc-RNAseq dataset of a cohort of treatment-naïve CRC patients. Conditional deletion of Cxcr3 in NKp46+ cells and antibody-mediated depletion of metastasis-associated macrophages markedly impair CD49a+NK cell development, indicating that CXCR3 and macrophages contribute to efficient NK cell localization and polarization in liver metastasis. Conversely, CXCR3neg NK cells maintain a CD49a- phenotype in metastasis with reduced parenchymal infiltration and tumor killing capacity. Furthermore, CD49a+NK cell accumulation is impaired in an independent SL4-induced CRC metastasis model, which fails to accumulate CXCL9+ macrophages. Together, our results highlight a role for CXCR3/ligand axis in promoting macrophage-dependent NK cell accumulation and functional sustenance in liver metastasis from colorectal cancer.

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