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Project description:The therapeutic potential for human type 2 innate lymphoid cells (ILC2s) has been underexplored. While not observed in mouse ILC2s, we have found that human ILC2s secrete granzyme B (GZMB) and directly lyse tumor cells by inducing pyroptosis and/or apoptosis, which is governed by a DNAM-1CD112/CD155 interaction that inactivates FOXO1. Over time, the high surface density expression of CD155 in AML impairs expression of DNAM-1 and GZMB, thus allowing for immune evasion. We describe a reliable platform capable of up to 2,000-fold expansion of human ILC2s within 4 weeks, whose molecular and cellular ILC2 profile has been validated by single-cell RNA sequencing. In both AML and solid tumor models, exogenously administered expanded human ILC2s show significant antitumor effects in vivo. Collectively, we demonstrate previously unreported properties of human ILC2s and identify this innate immune cell subset as a new member of the cytolytic immune effector cell family.
2024-01-01 | GSE247207 | GEO
Project description:The therapeutic potential for human type 2 innate lymphoid cells (ILC2s) has been underexplored. While not observed in mouse ILC2s, we have found that human ILC2s secrete granzyme B (GZMB) and directly lyse tumor cells by inducing pyroptosis and/or apoptosis, which is governed by a DNAM-1CD112/CD155 interaction that inactivates FOXO1. Over time, the high surface density expression of CD155 in AML impairs expression of DNAM-1 and GZMB, thus allowing for immune evasion. We describe a reliable platform capable of up to 2,000-fold expansion of human ILC2s within 4 weeks, whose molecular and cellular ILC2 profile has been validated by single-cell RNA sequencing. In both AML and solid tumor models, exogenously administered expanded human ILC2s show significant antitumor effects in vivo. Collectively, we demonstrate previously unreported properties of human ILC2s and identify this innate immune cell subset as a new member of the cytolytic immune effector cell family.
2024-01-01 | GSE247206 | GEO
Project description:The therapeutic potential for human type 2 innate lymphoid cells (ILC2s) has been underexplored. While not observed in mouse ILC2s, we have found that human ILC2s secrete granzyme B (GZMB) and directly lyse tumor cells by inducing pyroptosis and/or apoptosis, which is governed by a DNAM-1-CD112/CD155 interaction that inactivates FOXO1. Over time, the high surface density expression of CD155 in AML impairs expression of DNAM-1 and GZMB, thus allowing for immune evasion. We describe a reliable platform capable of up to 2,000-fold expansion of human ILC2s within 4 weeks, whose molecular and cellular ILC2 profile has been validated by single-cell RNA sequencing. In both AML and solid tumor models, exogenously administered expanded human ILC2s show significant antitumor effects in vivo. Collectively, we demonstrate previously unreported properties of human ILC2s and identify this innate immune cell subset as a new member of the cytolytic immune effector cell family.
2024-01-01 | GSE247205 | GEO
Project description:Although a number of studies have recently explored the contribution of the adaptive immunity in IL-33-mediated antitumor effects, innate immune involvement has been poorly characterized. Utilizing Rag1-/- mice (lacking T and B lymphocytes), we show in this study that either systemic administration of recombinant IL-33 or ectopic expression of IL-33 in melanoma cells is sufficient to inhibit tumor growth independent of adaptive antitumor immunity. We have demonstrated that IL-33-mediated antitumor effects depend on expansion and activation of NK cells. Interestingly, IL-33 also promoted the expansion of active type 2 innate lymphoid cells (ILC2s) via its receptor, ST2, which in turn inhibited NK activation and cytotoxicity. This IL-33-induced ILC2 activity coincided with greater expression of the immunosuppressive ectoenzyme CD73. Removal of CD73 from ILC2s in culture with NK cells resulted in markedly increased activation levels in NK cells, offering a potential mechanism by which ILC2s might suppress NK cell-mediated tumor killing. Thus, our data reveal an important contribution of IL-33-induced ILC2 to tumor growth by weakening NK cell activation and tumor killing, regardless of adaptive immunity.
| S-EPMC6264920 | biostudies-literature
Project description:Group 1 Innate Lymphoid Cells (which include Natural Killer cells and ILC1s) aid in gut anti-bacterial defense through the production of IFNγ, which is critical for mobilizing protective responses against enteric pathogens. When intestinal epithelial barrier integrity is compromised, commensal bacteria are likely to translocate from the gut lumen into the lamina propria. Few studies have addressed the mechanisms by which commensal bacteria impact the function of gut Group 1 ILCs, especially ILC1s. Utilizing an in vitro human colonic lamina propria mononuclear cell (LPMC) model, we evaluated Group 1 ILC cytokine and cytolytic protein production in response to a panel of enteric Gram-positive and Gram-negative commensal and pathogenic bacteria. IFNγ-production by NK cells and ILC1s was significantly increased after LPMC exposure to Gram-negative commensal or pathogenic bacteria, but not after exposure to the Gram-positive bacteria commensals tested. Stimulation of IFNγ production from Group 1 ILCs was not through direct recognition of bacteria by NK cells or ILC1s, but rather required accessory cells within the LPMC population. Myeloid dendritic cells generated IL-12p70, IL-18, and IL-1β upon exposure to enteric bacteria and these cytokines contributed to Group 1 ILC production of IFNγ. Furthermore, Gram-negative commensal or pathogenic bacteria induced significant expression of Granzyme B in NK cells and ILC1s. Overall, these data demonstrate that some enteric commensal bacteria indirectly induce inflammatory cytokine production and cytolytic protein expression from human colonic Group 1 ILCs, a process which could contribute to inflammation in the setting of microbial translocation.
| S-EPMC7524156 | biostudies-literature
Project description:Granzymes (Gzm) are serine proteases, contained into the secretory granules of cytotoxic cells, responsible for the cell-mediated cytotoxicity (CMC) against tumor cells and intracellular pathogens such as virus and bacteria. In fish, they have received little attention to their existence, classification or functional characterization. Therefore, we aimed to identify and evaluate their functional and transcriptomic relevance in the innate CMC activity of two relevant teleost fish species, gilthead seabream and European sea bass. Afterwards, we wanted to focus on their regulation upon nodavirus (NNV) infection, a virus that causes great mortalities to sea bass specimens while seabream is resistant. In this study, we have identified genes encoding GzmA and GzmB in both seabream and sea bass, as well as GzmM in seabream, which showed good phylogenetic relation to their mammalian orthologs. In addition, we found enzymatic activity related to tryptase (GzmA and/or GzmK), aspartase (GzmB), metase (GzmM), or chymase (GzmH) in resting head-kidney leucocytes (HKLs), with the following order of activity: GzmA/K ~ GzmM >> GzmH >>> GzmB. In addition, during innate CMC assays consisting on HKLs exposed to either mock- or NNV-infected target cells, though all the granzyme transcripts were increased only the tryptase activity did. Thus, our data suggest a high functional activity of GzmA/K in the innate CMC and a marginal one for GzmB. Moreover, GzmB activity was detected into target cells during the CMC assays. However, the percentage of target cells with GzmB activity after the CMC assays was about 10-fold lower than the death target cells, demonstrating that GzmB is not the main inductor of cell death. Moreover, in in vivo infection with NNV, gzm transcription is differently regulated depending on the fish species, genes and tissues. However, the immunohistochemistry study revealed an increased number of GzmB stained cells and areas in the brain of seabream after NNV infection, which was mainly associated with the lesions detected. Further studies are needed to ascertain the molecular nature, biological function and implication of fish granzymes in the CMC activity, and in the antiviral defense in particular.
| S-EPMC6834543 | biostudies-literature
Project description:Innate Lymphoid Cells (ILCs) play a key role in tissue mediated immunity and can be controlled by co-receptor signaling. Here we define a subset of ILCs that are Tbet+NK1.1- and are present within the tumor microenvironment (TME). We show programmed death-1 receptor (PD-1) expression on ILCs within TME is found in Tbet+NK1.1-ILCs. PD-1 significantly controlled the proliferation and function of Tbet+NK1.1-ILCs in multiple murine and human tumors. We found tumor derived lactate enhanced PD-1 expression on Tbet+NK1.1-ILCs within the TME, which resulted in dampened mTOR signaling along with increased fatty acid uptake. In line with these metabolic changes, PD-1 deficient Tbet+NK1.1-ILCs expressed significantly increased IFNg, granzyme B and K. Furthermore, PD-1 deficient Tbet+NK1.1- ILCs contributed towards diminished tumor growth in an experimental murine model of melanoma. These data demonstrate that PD-1 can regulate anti-tumor responses of Tbet+NK1.1-ILCs within the tumor microenvironment.
2023-04-11 | GSE229288 | GEO
Project description:Simple Summary Multiple myeloma (MM) is the second most common haematological malignancy. Despite huge progress associated with the introduction of new antimyeloma drugs, MM remains an incurable disease. In this review, we discuss the role of the innate lymphoid system, its role in the pathogenesis of the disease, and the mechanisms by which innate lymphoid cells (ILC) can theoretically achieve therapeutic benefit in MM treatment. Abstract Innate lymphoid cells (ILCs) are a recently identified family of lymphocyte-like cells lacking a specific antigen receptor. They are part of the innate immune system. They play a key role in tissue homeostasis and also control inflammatory and neoplastic processes. In response to environmental stimuli, ILCs change their phenotype and functions, and influence the activity of other cells in the microenvironment. ILC dysfunction can lead to a wide variety of diseases, including cancer. ILC can be divided into three subgroups: ILC Group 1, comprising NK cells and ILC1; Group 2, including ILC2 alone; and Group 3, containing Lymphoid Tissue inducers (LTi) and ILC3 cells. While Group 1 ILCs mainly exert antitumour activity, Group 2 and Group 3 ILCs are protumorigenic in nature. A growing body of preclinical and clinical data support the role of ILCs in the pathogenesis of multiple myeloma (MM). Therefore, targeting ILCs may be of clinical benefit. In this manuscript, we review the available data on the role of ILCs in MM immunology and therapy.
| S-EPMC8507621 | biostudies-literature
Project description:BackgroundLung carcinoma is still associated with high rates of morbidity and mortality despite the advances in cancer therapy achieved in last decades. Recent studies showed that immune responses played a crucial role in the developments of cancers including lung cancer. Type 1 immune response could promote classical activated macrophages (CAMs) with antitumor properties. On the contrast, type 2 immune response could lead to the polarization of alternatively activated macrophages (AAMs) which could promote the growth and metastasis of tumor. Our previous research showed that vitamin A deficiency could promote the type 2 immune response but not the type 1 immune response. Whether vitamin A deficiency has detrimental effect for lung carcinoma need further investigate.AimTo investigate the effect of vitamin A deficiency in lung cancer and the potential mechanisms.MethodsMice were fed with normal diet or vitamin A deficiency diet for 2 weeks, and then, Lewis lung cancer (LLC) cells dissolved in Matrigel Matrix were planted on the left lower lope of lungs. Mice were sacrificed 28 days after the plantation of tumor cells, the tumor size, cytokine profile in bronchoalveolar lavage fluid (BALF), numbers of type 2 innate lymphoid cells (ILC2s), and macrophage phenotypes in the lung were measured. The overall survival rate was also monitored throughout the experiments.ResultsVitamin A deficiency diet fed tumor-bearing mice have lower survival rate (? 2 = 6.862, p < 0.001), larger tumor size (t = 2.651, p < 0.05), more ILC2s (t = 7.680, p < 0.001), and AAMs (t = 6.315, p < 0.001) in the lung tissue; also, type 2 cytokines concentrations in the BALF were higher compared to normal diet fed ones.ConclusionVitamin A deficiency could promote the pathogeneses of lung carcinoma via induction of ILC2s and polarizing AAMs.
| S-EPMC6475724 | biostudies-literature
Project description:Sex hormones regulate many autoimmune and inflammatory diseases, including asthma. As adults, asthma prevalence is 2-fold greater in women compared to men. The number of group 2 innate lymphoid cells (ILC2) is increased in patients with asthma, and we investigate how testosterone attenuates ILC2 function. In patients with moderate to severe asthma, we determine that women have an increased number of circulating ILC2 compared to men. ILC2 from adult female mice have increased IL-2-mediated ILC2 proliferation versus ILC2 from adult male mice, as well as pre-pubescent females and males. Further, 5?-dihydrotestosterone, a hormone downstream of testosterone, decreases lung ILC2 numbers and IL-5 and IL-13 expression from ILC2. In vivo, testosterone attenuated Alternaria-extract-induced IL-5+ and IL-13+ ILC2 numbers and lung eosinophils by intrinsically decreasing lung ILC2 numbers, as well as by decreasing expression of IL-33 and thymic stromal lymphopoietin (TSLP), ILC2-stimulating cytokines. Collectively, these findings provide a foundational understanding of sexual dimorphism in ILC2 function.
| S-EPMC5731254 | biostudies-literature