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Nature Reviews. Immunology Nov 2022More than a decade ago, type 2 innate lymphoid cells (ILC2s) were discovered to be members of a family of innate immune cells consisting of five subsets that form a... (Review)
Review
More than a decade ago, type 2 innate lymphoid cells (ILC2s) were discovered to be members of a family of innate immune cells consisting of five subsets that form a first line of defence against infections before the recruitment of adaptive immune cells. Initially, ILC2s were implicated in the early immune response to parasitic infections, but it is now clear that ILC2s are highly diverse and have crucial roles in the regulation of tissue homeostasis and repair. ILC2s can also regulate the functions of other type 2 immune cells, including T helper 2 cells, type 2 macrophages and eosinophils. Dysregulation of ILC2s contributes to type 2-mediated pathology in a wide variety of diseases, potentially making ILC2s attractive targets for therapeutic interventions. In this Review, we focus on the spectrum of ILC2 phenotypes that have been described across different tissues and disease states with an emphasis on human ILC2s. We discuss recent insights in ILC2 biology and suggest how this knowledge might be used for novel disease treatments and improved human health.
Topics: Humans; Immunity, Innate; Lymphocytes; Th2 Cells
PubMed: 35354980
DOI: 10.1038/s41577-022-00704-5 -
Journal For Immunotherapy of Cancer Dec 2022The immunogenic nature of metastatic colorectal cancer (CRC) with high microsatellite instability (MSI-H) underlies their responsiveness to immune checkpoint blockade...
BACKGROUND
The immunogenic nature of metastatic colorectal cancer (CRC) with high microsatellite instability (MSI-H) underlies their responsiveness to immune checkpoint blockade (ICB). However, resistance to ICB is commonly observed, and is associated with the presence of peritoneal-metastases and ascites formation. The mechanisms underlying this site-specific benefit of ICB are unknown.
METHODS
We created a novel model for spontaneous multiorgan metastasis in MSI-H CRC tumors by transplanting patient-derived organoids (PDO) into the cecum of humanized mice. Anti-programmed cell death protein-1 (PD-1) and anti-cytotoxic T-lymphocytes-associated protein 4 (CTLA-4) ICB treatment effects were analyzed in relation to the immune context of primary tumors, liver metastases, and peritoneal metastases. Immune profiling was performed by immunohistochemistry, flow cytometry and single-cell RNA sequencing. The role of B cells was assessed by antibody-mediated depletion. Immunosuppressive cytokine levels (interleukin (IL)-10, transforming growth factor (TGF)b1, TGFb2, TGFb3) were determined in ascites and serum samples by ELISA.
RESULTS
PDO-initiated primary tumors spontaneously metastasized to the liver and the peritoneum. Peritoneal-metastasis formation was accompanied by the accumulation of ascites. ICB completely cleared liver metastases and reduced primary tumor mass but had no effect on peritoneal metastases. This mimics clinical observations. After therapy discontinuation, primary tumor masses progressively decreased, but peritoneal metastases displayed unabated growth. Therapy efficacy correlated with the formation of tertiary lymphoid structures (TLS)-containing B cells and juxtaposed T cells-and with expression of an interferon-γ signature together with the B cell chemoattractant CXCL13. B cell depletion prevented liver-metastasis clearance by anti-CTLA-4 treatment. Peritoneal metastases were devoid of B cells and TLS, while the T cells in these lesions displayed a dysfunctional phenotype. Ascites samples from patients with cancer with peritoneal metastases and from the mouse model contained significantly higher levels of IL-10, TGFb1, TGFb2 and TGFb3 than serum samples.
CONCLUSIONS
By combining organoid and humanized mouse technologies, we present a novel model for spontaneous multiorgan metastasis by MSI-H CRC, in which the clinically observed organ site-dependent benefit of ICB is recapitulated. Moreover, we provide empirical evidence for a critical role for B cells in the generation of site-dependent antitumor immunity following anti-CTLA-4 treatment. High levels of immunosuppressive cytokines in ascites may underlie the observed resistance of peritoneal metastases to ICB.
Topics: Mice; Animals; Immune Checkpoint Inhibitors; Transforming Growth Factor beta3; Peritoneum; Ascites; Peritoneal Neoplasms; Cytokines; Liver Neoplasms; Colorectal Neoplasms
PubMed: 36543378
DOI: 10.1136/jitc-2022-005345 -
Immunity Feb 2021The role of innate immune cells in allergen immunotherapy that confers immune tolerance to the sensitizing allergen is unclear. Here, we report a role of... (Randomized Controlled Trial)
Randomized Controlled Trial
The role of innate immune cells in allergen immunotherapy that confers immune tolerance to the sensitizing allergen is unclear. Here, we report a role of interleukin-10-producing type 2 innate lymphoid cells (IL-10 ILC2s) in modulating grass-pollen allergy. We demonstrate that KLRG1 but not KLRG1 ILC2 produced IL-10 upon activation with IL-33 and retinoic acid. These cells attenuated Th responses and maintained epithelial cell integrity. IL-10 KLRG1 ILC2s were lower in patients with grass-pollen allergy when compared to healthy subjects. In a prospective, double-blind, placebo-controlled trial, we demonstrated that the competence of ILC2 to produce IL-10 was restored in patients who received grass-pollen sublingual immunotherapy. The underpinning mechanisms were associated with the modification of retinol metabolic pathway, cytokine-cytokine receptor interaction, and JAK-STAT signaling pathways in the ILCs. Altogether, our findings underscore the contribution of IL-10 ILC2s in the disease-modifying effect by allergen immunotherapy.
Topics: Adult; Allergens; Double-Blind Method; Female; Humans; Immune Tolerance; Immunity, Innate; Interleukin-10; Janus Kinases; Lectins, C-Type; Lymphocytes; Male; Middle Aged; Placebo Effect; Poaceae; Pollen; Receptors, Immunologic; Rhinitis, Allergic, Seasonal; STAT Transcription Factors; Signal Transduction; Sublingual Immunotherapy; Th2 Cells; Treatment Outcome; Vitamin A; Young Adult
PubMed: 33450188
DOI: 10.1016/j.immuni.2020.12.013 -
British Dental Journal Jul 2020
PubMed: 32651484
DOI: 10.1038/s41415-020-1859-1 -
Human Reproduction Open 2022How should ART/preimplantation genetic testing (PGT) centres manage the detection of chromosomal mosaicism following PGT?
STUDY QUESTION
How should ART/preimplantation genetic testing (PGT) centres manage the detection of chromosomal mosaicism following PGT?
SUMMARY ANSWER
Thirty good practice recommendations were formulated that can be used by ART/PGT centres as a basis for their own policy with regards to the management of 'mosaic' embryos.
WHAT IS KNOWN ALREADY
The use of comprehensive chromosome screening technologies has provided a variety of data on the incidence of chromosomal mosaicism at the preimplantation stage of development and evidence is accumulating that clarifies the clinical outcomes after transfer of embryos with putative mosaic results, with regards to implantation, miscarriage and live birth rates, and neonatal outcomes.
STUDY DESIGN SIZE DURATION
This document was developed according to a predefined methodology for ESHRE good practice recommendations. Recommendations are supported by data from the literature, a large survey evaluating current practice and published guidance documents. The literature search was performed using PubMed and focused on studies published between 2010 and 2022. The survey was performed through a web-based questionnaire distributed to members of the ESHRE special interest groups (SIG) Reproductive Genetics and Embryology, and the ESHRE PGT Consortium members. It included questions on ART and PGT, reporting, embryo transfer policy and follow-up of transfers. The final dataset represents 239 centres.
PARTICIPANTS/MATERIALS SETTING METHODS
The working group (WG) included 16 members with expertise on the ART/PGT process and chromosomal mosaicism. The recommendations for clinical practice were formulated based on the expert opinion of the WG, while taking into consideration the published data and results of the survey.
MAIN RESULTS AND THE ROLE OF CHANCE
Eighty percent of centres that biopsy three or more cells report mosaicism, even though only 66.9% of all centres have validated their technology and only 61.8% of these have validated specifically for the calling of chromosomal mosaicism. The criteria for designating mosaicism, reporting and transfer policies vary significantly across the centres replying to the survey. The WG formulated recommendations on how to manage the detection of chromosomal mosaicism in clinical practice, considering validation, risk assessment, designating and reporting mosaicism, embryo transfer policies, prenatal testing and follow-up. Guidance is also provided on the essential elements that should constitute the consent forms and the genetic report, and that should be covered in genetic counselling. As there are several unknowns in chromosomal mosaicism, it is recommended that PGT centres monitor emerging data on the topic and adapt or refine their policy whenever new insights are available from evidence.
LIMITATIONS REASONS FOR CAUTION
Rather than providing instant standardized advice, the recommendations should help ART/PGT centres in developing their own policy towards the management of putative mosaic embryos in clinical practice.
WIDER IMPLICATIONS OF THE FINDINGS
This document will help facilitate a more knowledge-based approach for dealing with chromosomal mosaicism in different centres. In addition to recommendations for clinical practice, recommendations for future research were formulated. Following up on these will direct research towards existing research gaps with direct translation to clinical practice. Emerging data will help in improving guidance, and a more evidence-based approach of managing chromosomal mosaicism.
STUDY FUNDING/COMPETING INTERESTS
The WG received technical support from ESHRE. M.D.R. participated in the EQA special advisory group, outside the submitted work, and is the chair of the PGT WG of the Belgian society for human genetics. D.W. declared receiving salary from Juno Genetics, UK. A.C. is an employee of Igenomix, Italy and C.R. is an employee of Igenomix, Spain. C.S. received a research grant from FWO, Belgium, not related to the submitted work. I.S. declared being a Co-founder of IVFvision Ltd, UK. J.R.V. declared patents related to 'Methods for haplotyping single-cells' and 'Haplotyping and copy number typing using polymorphic variant allelic frequencies', and being a board member of Preimplantation Genetic Diagnosis International Society (PGDIS) and International Society for Prenatal Diagnosis (ISPD). K.S. reported being Chair-elect of ESHRE. The other authors had nothing to disclose.
DISCLAIMER
PubMed: 36349144
DOI: 10.1093/hropen/hoac044 -
Journal For Immunotherapy of Cancer Aug 2020Treatment of metastatic melanoma with autologous tumor infiltrating lymphocytes (TILs) is currently applied in several centers. Robust and remarkably consistent overall...
UNLABELLED
Treatment of metastatic melanoma with autologous tumor infiltrating lymphocytes (TILs) is currently applied in several centers. Robust and remarkably consistent overall response rates, of around 50% of treated patients, have been observed across hospitals, including a substantial fraction of durable, complete responses.
PURPOSE
Execute a phase I/II feasibility study with TIL therapy in metastatic melanoma at the Netherlands Cancer Institute, with the goal to assess feasibility and potential value of a randomized phase III trial.
EXPERIMENTAL
Ten patients were treated with TIL therapy. Infusion products and peripheral blood samples were phenotypically characterized and neoantigen reactivity was assessed. Here, we present long-term clinical outcome and translational data on neoantigen reactivity of the T cell products.
RESULTS
Five out of 10 patients, who were all anti-PD-1 naïve at time of treatment, showed an objective clinical response, including two patients with a complete response that are both ongoing for more than 7 years. Immune monitoring demonstrated that neoantigen-specific T cells were detectable in TIL infusion products from three out of three patients analyzed. For six out of the nine neoantigen-specific T cell responses detected in these TIL products, T cell response magnitude increased significantly in the peripheral blood compartment after therapy, and neoantigen-specific T cells were detectable for up to 3 years after TIL infusion.
CONCLUSION
The clinical results from this study confirm the robustness of TIL therapy in metastatic melanoma and the potential role of neoantigen-specific T cell reactivity. In addition, the data from this study supported the rationale to initiate an ongoing multicenter phase III TIL trial.
Topics: Adult; Aged; Female; Follow-Up Studies; Humans; Lymphocytes, Tumor-Infiltrating; Male; Melanoma; Middle Aged; T-Lymphocytes
PubMed: 32753545
DOI: 10.1136/jitc-2020-000848 -
Seminars in Immunology Nov 2022The family of innate lymphoid cells (ILCs) are composed of five canonical subsets, NK cells, ILC1, ILC2, ILC3 and Lymphoid tissue inducer cells. ILCs have important... (Review)
Review
The family of innate lymphoid cells (ILCs) are composed of five canonical subsets, NK cells, ILC1, ILC2, ILC3 and Lymphoid tissue inducer cells. ILCs have important functions in early stages of immune response towards infectious agents. ILCs are highly plastic enabling rapid modification of their functions dependent on the type of microbe and tissue environment to optimally counter these microbes. Data that still accumulate in a rapid pace indicate that these cells are also involved in immunity against tumor cells. Paradoxically ILC subsets have been shown to have tumor suppressing and tumor promoting activities. In this brief review we provide a snapshot of our current knowledge of characteristics and functions of tumor infiltrating ILC subsets and speculate on how these cells can be harnessed to mediate anti-tumor immunity.
Topics: Humans; Immunity, Innate; Lymphocytes; Killer Cells, Natural; T-Lymphocytes, Helper-Inducer; Neoplasms; Lymphoid Tissue; Lymphocyte Subsets
PubMed: 36306660
DOI: 10.1016/j.smim.2022.101654 -
Cell Stem Cell Dec 2022It is well established that human pluripotent stem cells (hPSCs) can acquire genetic and epigenetic changes during culture in vitro. Given the increasing use of hPSCs... (Review)
Review
It is well established that human pluripotent stem cells (hPSCs) can acquire genetic and epigenetic changes during culture in vitro. Given the increasing use of hPSCs in research and therapy and the vast expansion in the number of hPSC lines available for researchers, the International Society for Stem Cell Research has recognized the need to reassess quality control standards for ensuring the genetic integrity of hPSCs. Here, we summarize current knowledge of the nature of recurrent genetic and epigenetic variants in hPSC culture, the methods for their detection, and what is known concerning their effects on cell behavior in vitro or in vivo. We argue that the potential consequences of low-level contamination of cell therapy products with cells bearing oncogenic variants are essentially unknown at present. We highlight the key challenges facing the field with particular reference to safety assessment of hPSC-derived cellular therapeutics.
Topics: Humans; Epigenomics; Pluripotent Stem Cells; Stem Cell Research; Oncogenes; Epigenesis, Genetic
PubMed: 36459966
DOI: 10.1016/j.stem.2022.11.006 -
Current Opinion in Immunology Feb 2021Five subsets of ILCs are extensively described, Lymphoid Tissue inducer (LTi) cells, cytotoxic NK cells and non-cytotoxic helper ILC1s, ILC2s and ILC3s. So far, the main... (Review)
Review
Five subsets of ILCs are extensively described, Lymphoid Tissue inducer (LTi) cells, cytotoxic NK cells and non-cytotoxic helper ILC1s, ILC2s and ILC3s. So far, the main focus has been on the potent cytokine production by helper ILCs and their plastic nature that allows them to switch function and phenotype upon environmental changes. Recent advances in the field indicate the presence of cytotoxic helper ILCs that are distinct from conventional NK cells. In humans, these cytotoxic ILCs can develop from conventional helper ILCs whereas in mice this remains to be elucidated. In this review we discuss the identification, development and function of cytotoxic helper ILCs subsets in humans and mice.
Topics: Animals; Humans; Immunity, Innate; Killer Cells, Natural; Lymphocytes
PubMed: 32971468
DOI: 10.1016/j.coi.2020.08.007