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Project description:Type I innate lymphoid cells (ILC1s) are critical regulators of inflammation and immunity in mammalian tissues. However, their functional roles in cancer are largely undefined. We found that a high concentration of normal murine ILC1s induced leukemia stem cell (LSC) apoptosis. At a lower concentration, ILC1s prevented LSCs from differentiating into leukemia progenitors and promoted their differentiation into non-leukemic cells, thus blocking the production of terminal myeloid blasts. All of these effects, which required ILC1s to produce interferon-γ after cell–cell contact with LSCs, converged to suppress leukemogenesis in vivo. Conversely, ILC1s’ anti-leukemia potential waned when JAK-STAT and PI3K-AKT signaling was inhibited. The relevant anti-leukemic properties of normal ILC1s were operative in humans and impaired in AML patients. Collectively, our findings reveal crucial functions of ILC1s as anti-cancer immune cells seemingly suitable for AML immunotherapy, and provide a new potential strategy to treat AML and/or prevent relapse of the disease.
2022-03-19 | GSE198782 | GEO
Project description:Type I innate lymphoid cells (ILC1s) are critical regulators of inflammation and immunity in mammalian tissues. However, their functional roles in cancer are largely undefined. We found that a high concentration of normal murine ILC1s induced leukemia stem cell (LSC) apoptosis. At a lower concentration, ILC1s prevented LSCs from differentiating into leukemia progenitors and promoted their differentiation into non-leukemic cells, thus blocking the production of terminal myeloid blasts. All of these effects, which required ILC1s to produce interferon-γ after cell–cell contact with LSCs, converged to suppress leukemogenesis in vivo. Conversely, ILC1s’ anti-leukemia potential waned when JAK-STAT and PI3K-AKT signaling was inhibited. The relevant anti-leukemic properties of normal ILC1s were operative in humans and impaired in AML patients. Collectively, our findings reveal crucial functions of ILC1s as anti-cancer immune cells seemingly suitable for AML immunotherapy, and provide a new potential strategy to treat AML and/or prevent relapse of the disease.
2022-03-19 | GSE198781 | GEO
Project description:Type I Innate Lymphoid Cells Control Leukemia Stem Cell Fate and Limit Development of Acute Myeloid Leukemia
| PRJNA816867 | ENA
Project description:Type I Innate Lymphoid Cells Control Leukemia Stem Cell Fate and Limit Development of Acute Myeloid Leukemia [2]
| PRJNA816876 | ENA
Project description:Type I Innate Lymphoid Cells Control Leukemia Stem Cell Fate and Limit Development of Acute Myeloid Leukemia [1]
| PRJNA816860 | ENA
Project description:Type I innate lymphoid cells (ILC1s) are critical regulators of inflammation and immunity in mammalian tissues. However, their function in cancer is mostly undefined. Here, we show that a high density of ILC1s induces leukemia stem cell (LSC) apoptosis in mice. At a lower density, ILC1s prevent LSCs from differentiating into leukemia progenitors and promote their differentiation into non-leukemic cells, thus blocking the production of terminal myeloid blasts. All of these effects, which require ILC1s to produce interferon-γ after cell-cell contact with LSCs, converge to suppress leukemogenesis in vivo. Conversely, the antileukemia potential of ILC1s wanes when JAK-STAT or PI3K-AKT signaling is inhibited. The relevant antileukemic properties of ILC1s are also functional in healthy individuals and impaired in individuals with acute myeloid leukemia (AML). Collectively, these findings identify ILC1s as anticancer immune cells that might be suitable for AML immunotherapy and provide a potential strategy to treat AML and prevent relapse of the disease.
| S-EPMC9106917 | biostudies-literature
Project description:NK cells are known to be developmentally blocked and functionally inhibited in patients with acute myeloid leukemia (AML), resulting in poor clinical outcomes. In this study, we demonstrate that whereas NK cells are inhibited, closely related type 1 innate lymphoid cells (ILC1s) are enriched in the bone marrow of leukemic mice and in patients with AML. Because NK cells and ILC1s share a common precursor (ILCP), we asked if AML acts on the ILCP to alter developmental potential. A combination of ex vivo and in vivo studies revealed that AML skewing of the ILCP toward ILC1s and away from NK cells represented a major mechanism of ILC1 generation. This process was driven by AML-mediated activation of the aryl hydrocarbon receptor (AHR), a key transcription factor in ILCs, as inhibition of AHR led to decreased numbers of ILC1s and increased NK cells in the presence of AML. These results demonstrate a mechanism of ILC developmental skewing in AML and support further preclinical study of AHR inhibition in restoring normal NK cell development and function in the setting of AML.
| S-EPMC8429221 | biostudies-literature
Project description:Natural killer (NK) cells are known to be able to kill established tumor cell lines, but important caveats remain regarding their roles in the detection and elimination of developing primary tumors. Using a genetic model of selective ILC1 and NK cell deficiency, we showed that these cells were dispensable for tumor immunosurveillance and immunoediting in the MCA-induced carcinogenesis model. However, we were able to generate primary cell lines derived from MCA-induced tumors with graded sensitivity to NK1.1+ cells (including NK cells and ILC1). This differential sensitivity was associated neither with a modulation of intratumoral NK cell frequency, nor the capacity of tumor cells to activate NK cells. Instead, ILC1 infiltration into the tumor was found to be a critical determinant of NK1.1+ cell-dependent tumor growth. Finally, bulk tumor RNAseq analysis identified a gene expression signature associated with tumor sensitivity to NK1.1+ cells. ILC1 therefore appear to play an active role in inhibiting the antitumoral immune response, prompting to evaluate the differential tumor infiltration of ILC1 and NK cells in patients to optimize the harnessing of immunity in cancer therapies.
| S-EPMC8637113 | biostudies-literature
Project description:Type-2 innate lymphoid cells (ILC2) are a prominent source of type II cytokines and are found constitutively at mucosal surfaces and in visceral adipose tissue. Despite their role in limiting obesity, how ILC2s respond to high fat feeding is poorly understood, and their direct influence on the development of atherosclerosis has not been explored. Here, we show that ILC2 are present in para-aortic adipose tissue and lymph nodes and display an inflammatory-like phenotype atypical of adipose resident ILC2. High fat feeding alters both the number of ILC2 and their type II cytokine production. Selective genetic ablation of ILC2 in Ldlr-/- mice accelerates the development of atherosclerosis, which is prevented by reconstitution with wild type but not Il5-/- or Il13-/- ILC2. We conclude that ILC2 represent a major innate cell source of IL-5 and IL-13 required for mounting atheroprotective immunity, which can be altered by high fat diet.
| S-EPMC5467269 | biostudies-literature
Project description:Eosinophils are specialized myeloid cells associated with allergy and helminth infections. Blood eosinophils demonstrate circadian cycling, as described over 80?years ago, and are abundant in the healthy gastrointestinal tract. Although a cytokine, interleukin (IL)-5, and chemokines such as eotaxins mediate eosinophil development and survival, and tissue recruitment, respectively, the processes underlying the basal regulation of these signals remain unknown. Here we show that serum IL-5 levels are maintained by long-lived type 2 innate lymphoid cells (ILC2) resident in peripheral tissues. ILC2 cells secrete IL-5 constitutively and are induced to co-express IL-13 during type 2 inflammation, resulting in localized eotaxin production and eosinophil accumulation. In the small intestine where eosinophils and eotaxin are constitutive, ILC2 cells co-express IL-5 and IL-13; this co-expression is enhanced after caloric intake. The circadian synchronizer vasoactive intestinal peptide also stimulates ILC2 cells through the VPAC2 receptor to release IL-5, linking eosinophil levels with metabolic cycling. Tissue ILC2 cells regulate basal eosinophilopoiesis and tissue eosinophil accumulation through constitutive and stimulated cytokine expression, and this dissociated regulation can be tuned by nutrient intake and central circadian rhythms.
| S-EPMC3795960 | biostudies-other