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ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE197577 | GEO | 2022/03/03

REPOSITORIES: GEO

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ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics.

Project description:BackgroundTriple negative breast cancer (TNBC) is the most lethal subtype of breast cancer due to its aggressive behavior and frequent development of resistance to chemotherapy. Although natural killer (NK) cell-based immunotherapy is a promising strategy for overcoming barriers to cancer treatment, the therapeutic efficacy of NK cells against TNBC is below expectations. E26 transformation-specific transcription factor ELK3 (ELK3) is highly expressed in TNBCs and functions as a master regulator of the epithelial-mesenchymal transition.MethodsTwo representative human TNBC cell lines, MDA-MB231 and Hs578T, were exposed to ELK3-targeting shRNA or an ELK3-expressing plasmid to modulate ELK3 expression. The downstream target genes of ELK3 were identified using a combined approach comprising gene expression profiling and molecular analysis. The role of ELK3 in determining the immunosensitivity of TNBC to NK cells was investigated in terms of mitochondrial fission-fusion transition and reactive oxygen species concentration both in vitro and in vivo.ResultsELK3-dependent mitochondrial fission-fusion status was linked to the mitochondrial superoxide concentration in TNBCs and was a main determinant of NK cell-mediated immune responses. We identified mitochondrial dynamics proteins of 51 (Mid51), a major mediator of mitochondrial fission, as a direct downstream target of ELK3 in TNBCs. Also, we demonstrated that expression of ELK3 correlated inversely with that of Mid51, and that the ELK3-Mid51 axis is associated directly with the status of mitochondrial dynamics. METABRIC analysis revealed that the ELK3-Mid51 axis has a direct effect on the immune score and survival of patients with TNBC.ConclusionsTaken together, the data suggest that NK cell responses to TNBC are linked directly to ELK3 expression levels, shedding new light on strategies to improve the efficacy of NK cell-based immunotherapy of TNBC.

| S-EPMC9305827 | biostudies-literature

ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics [RNA-seq]

Project description:We demostrated that ELK3-Mid51 axis in TNBCs mediate mitochondrial dynamics determines concentration of reactive oxygen species that is linked to the immune sensitivity to cytotoxicity of NK cells.

2022-03-03 | GSE197575 | GEO

ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics [ChIP-seq]

2022-03-03 | GSE197572 | GEO

ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics

Project description:ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics

| PRJNA811114 | ENA

ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics [ChIP-seq]

Project description:ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics [ChIP-seq]

| PRJNA811117 | ENA

ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics [RNA-seq]

Project description:ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics [RNA-seq]

| PRJNA811116 | ENA

ELK3-CXCL16 axis determines natural killer cell cytotoxicity via the chemotactic activity of CXCL16 in triple negative breast cancer.

Project description:Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer because of its aggressive behavior and the limited therapeutic strategies available. In the last decade, immunotherapy has become a promising treatment to prolong survival in advanced solid cancers including TNBC. However, the efficacy of immunotherapy in solid cancers remains limited because solid tumors contain few tumor-infiltrating lymphocytes. Here, we show that targeting an ETS transcription factor ELK3 (ELK3) recruits immune cells including natural killer (NK) cells into tumors via the chemotactic activity of chemokine. ELK3 depletion increases CXCL16 expression level and promotes NK cell cytotoxicity through CXCL16-mediated NK cell recruitment in TNBC. In silico analysis showed that ELK3 is negatively correlated with CXCL16 expression in breast cancer patient samples. Low expression of ELK3 and high expression of CXCL16 were associated with a better prognosis. Low expression of ELK3 and high expression of CXCL16 were associated with increased expression of NK cell-related genes. Our findings demonstrate that the ELK3-CXCL16 axis modulates NK cell recruitment to increase NK cell cytotoxicity, suggesting that targeting the ELK3 gene could be an adjuvant strategy for increasing the efficacy of immunotherapy in TNBC.

| S-EPMC10026901 | biostudies-literature

An Interleukin-15 Superagonist Enables Antitumor Efficacy of Natural Killer Cells Against All Molecular Variants of SCLC.

Project description:IntroductionSCLC is a highly aggressive tumor with a 5-year survival rate of less than 6%. A heterogeneous disease, SCLC is classified into four subtypes that include tumors with neuroendocrine and non-neuroendocrine features. Immune checkpoint blockade has been recently added for the frontline treatment of SCLC; however, this therapy has only led to modest clinical improvements. The lack of clinical benefit in a cancer type known to have a high tumor mutational burden has been attributed to poor T-cell infiltration and low expression of MHC-class I in most SCLC tumors. In an attempt to devise a more effective immunotherapeutic regimen, this study investigated an alternate approach on the basis of the use of the clinical-stage interleukin-15 superagonist, N-803.MethodsPreclinical models of SCLC spanning all molecular subtypes were used to evaluate the susceptibility of SCLC to natural killer (NK)-mediated lysis in vitro, including NK cells activated by N-803. Antitumor activity of N-803 was evaluated in vivo with a xenograft model of SCLC.ResultsIn vitro and in vivo data revealed differences in susceptibility of SCLC subtypes to lysis by NK cells and that NK cells activated by N-803 effectively lyse SCLC tumor cells across all variant subtypes, regardless of their expression of MHC-class I.ConclusionsThese findings highlight the potential of a novel immune-based intervention using a cytokine-based therapeutic option for the treatment of SCLC. We hypothesize that N-803 may provide benefit to most patients with SCLC, including those with immunologically cold tumors lacking MHC expression.

| S-EPMC9974560 | biostudies-literature

Antitumor Immunity Exerted by Natural Killer and Natural Killer T Cells in the Liver.

Project description:The liver plays crucial roles in systemic immunity and greatly contributes to the systemic defense mechanism. Antitumor immunity in the liver is especially critical for the defense against systemic tumor cell dissemination. To achieve effective defense against metastatic tumor cells, liver immune cells with powerful cytotoxic activities construct a potent defense mechanism. In the liver, as compared with other organs, there is a significantly more intense percentage of innate immune lymphocytes, such as natural killer (NK) and NKT cells. These characteristic lymphocytes survey the portal blood transferred to the liver from the alimentary tract and eliminate malignant cells with their robust cytotoxic ability. Additionally, with their active cytokine-producing capacity, these innate lymphocytes initiate immunological sequences by adaptive immune cells. Therefore, they are crucial contributors to systemic antitumor immunity. These attractive immune cells help conduct a fundamental investigation of tumor immunity and act as a target of clinical measures for cancer therapies. This review discusses the mechanisms of these innate lymphocytes regarding recognition and cytotoxicity against tumor cells and the possibility of clinical applications for therapeutic measures.

| S-EPMC9917438 | biostudies-literature

Neurofibromin 1 Impairs Natural Killer T-Cell-Dependent Antitumor Immunity against a T-Cell Lymphoma.

Project description:Neurofibromin 1 (NF1) is a tumor suppressor gene encoding a Ras GTPase that negatively regulates Ras signaling pathways. Mutations in NF1 are linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. In terms of antitumor immunity, CD1d-dependent natural killer T (NKT) cells play an important role in the innate antitumor immune response. Generally, Type-I NKT cells protect (and Type-II NKT cells impair) host antitumor immunity. We have previously shown that CD1d-mediated antigen presentation to NKT cells is regulated by cell signaling pathways. To study whether a haploinsufficiency in NF1 would affect CD1d-dependent activation of NKT cells, we analyzed the NKT-cell population as well as the functional expression of CD1d in Nf1+/- mice. Nf1+/- mice were found to have similar levels of NKT cells as wildtype (WT) littermates. Interestingly, however, reduced CD1d expression was observed in Nf1+/- mice compared with their WT littermates. When inoculated with a T-cell lymphoma in vivo, Nf1+/- mice survived longer than their WT littermates. Furthermore, blocking CD1d in vivo significantly enhanced antitumor activity in WT, but not in Nf1+/- mice. In contrast, a deficiency in Type-I NKT cells increased antitumor activity in Nf1+/- mice, but not in WT littermates. Therefore, these data suggest that normal NF1 expression impairs CD1d-mediated NKT-cell activation and antitumor activity against a T-cell lymphoma.

| S-EPMC5760513 | biostudies-literature

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