Immunoregulatory effects of placenta-derived decidual stromal cells

Decidual stromal cells (DSCs) play a pivotal role in feto-maternal tolerance to prevent rejection of the fetus during pregnancy. This provides a rationale for immunomodulatory stromal cells from the placenta being isolated and used as cellular therapy for inflammatory conditions following hematopoietic stem cell transplantation (HSCT). The term placenta provides a ready source of cells, since this tissue is normally discarded after delivery. Stromal cells were isolated from different parts of the term placenta, specifically chorionic villi, umbilical cord, and the fetal membranes. DSCs isolated from the fetal membranes had a consistent immunosuppressive capacity in vitro comparable to that of bone marrow-derived mesenchymal stromal cells (MSCs). This immune suppression was partly contact-dependent. Factors of importance in this process were found to include interferon-γ (IFN-γ), prostaglandin E2, indoleamine-2,3-dioxygenase (IDO), and programmed death ligand 1 (PD-L1). In addition, IDO was found to play a role in the DSC-mediated induction of regulatory T cells (Tregs) in vitro. The addition of DSCs to the allogeneic setting in vitro also resulted in a reduction in the concentration of cytokines IFN-γ and interleukin (IL)-17, while the concentrations of IL-10 and IL-2 were elevated. There was also a correlation between increased IL-2 levels and reduced expression of the high-affinity IL-2 receptor on alloantigen-activated T cells. This was consistent with a reduced phosphorylation of STAT5 and reduced uptake of IL-2 in the cultures. The reduced sensitivity to IL-2 was not found to be correlated to an increased exhaustion state, based on expression of programmed death 1 (PD-1) and CD95. Further characterization of DSCs showed that they have limited differentiation capacity, that they are of maternal origin, and that they have high expression of co-inhibitory markers and integrins that are of importance for migration to inflamed tissue. The expression of these markers was elevated in the presence of external IFN-γ. In contrast, addition of IFN-γ did not increase the antiproliferative effect of DSCs in vitro. DSCs were expanded to high cell numbers at low passage number. These DSCs were then introduced as a treatment for severe graft-versus-host disease (GVHD), a common complication after HSCT with high mortality rates. In an initial pilot study, nine patients were treated with DSCs. In eight patients who could be evaluated, the overall response rate was 75% and three patients were alive six months after transplant. In a larger patient cohort, immune parameters were monitored up to four weeks after DSC intervention. The patients were divided into two groups, responders and non-responders, depending on GVHD status after DSC treatment. Increased plasma concentrations of IL-6, IL-8, and IP-10 distinctly differentiated the non-responders from the responders before DSC intervention. Although the expression of HLA-DR decreased over time in the CD4+ compartment of the responders, the same group had increasing expression of CCR9 in several cell subsets, including CD4+ T cells, B cells, and monocytes. The responders also had less naïve CD4+ T cells one week after DSC intervention. Thus, DSCs can be isolated from term placentas and can be expanded to high cell numbers at low passage number. The DSCs have immunomodulatory functions, mediated by several factors. DSCs may be used as a treatment for GVHD, and improvement in GVHD may be distinguished by a specific immune profile

Lymphocytes in Placental Tissues: Immune Regulation and Translational Possibilities for Immunotherapy

Immune modulation at the fetomaternal interface is crucial to ensure that the fetal allograft is not rejected. In the present review, the focus is to describe basic functions of lymphocyte populations and how they may contribute to fetomaternal immune regulation, as well as determining what proportions and effector functions of these cells are reported to be present in placental tissues in humans. Also explored is the possibility that unique cell populations at the fetomaternal interface may be targets for adoptive cell therapy. Increasing the understanding of immune modulation during pregnancy can give valuable insight into other established fields such as allogeneic hematopoietic stem cell transplantation and solid organ transplantation. In these settings, lymphocytes are key components that contribute to inflammation and rejection of either patient or donor tissues following transplantation. In contrast, an allogeneic fetus eludes rejection by the maternal immune system

Mucosal-Associated Invariant T Cells Display a Poor Reconstitution and Altered Phenotype after Allogeneic Hematopoietic Stem Cell Transplantation

International audienceNote sur Conseil d'Etat, Section, 30 juillet 2003, Association pour le développement de l'aquaculture en région Centre et autres, AJDA 2003, p. 1815, chron. Donnat et Casa

Mucosal-Associated Invariant T Cells Display a Poor Reconstitution and Altered Phenotype after Allogeneic Hematopoietic Stem Cell Transplantation

Mucosal-associated invariant T (MAIT) cells are innate-like T cells which are important in the defense against certain bacteria and yeast. The reconstitution of MAIT cells after allogeneic hematopoietic stem cell transplantation (HSCT) is not known. We investigated MAIT cell phenotype and function in 17 patients devoid of relapse and severe graft-versus-host disease (GvHD) in paired samples collected 1–2, 3–6, 12, and 24 months after transplantation. Data were compared to 17 healthy controls (HC), as well as 22 patients with acute GvHD grade 2–3. The frequency of MAIT cells within CD3+ cells was approximately 10-fold lower than in HC and did not increase over the 2 years following HSCT. MAIT cells in HSCT patients displayed an elevated expression of CD69 and intracellular granzyme B and were predominantly composed of CD4/CD8 double-negative cells. The expression of PD-1 on MAIT cells was low and did not change during the observational time, whereas the CD3+CD161dim/negTCRVα7.2dim/neg cells (non-MAIT T cells) displayed a high expression early after HSCT that decreased to normal levels at 24 months. MAIT cells collected 2–6 months post-HSCT showed an impaired IFN-γ and perforin response after bacterial stimulation, but the response was restored at 24 months. Patients with acute GvHD had similar proportions of MAIT cells as patients with grade 0–1, but consisted mainly of CD8+ cells. Finally, MAIT cells were more sensitive to cyclosporine A and sirolimus than non-MAIT T cells. To conclude, MAIT cell reconstitution following HSCT is deficient compared to non-MAIT T cells and GvHD grade ≥2 is not correlated with MAIT cell frequency. MAIT cell functionality was impaired early after HSCT, but restored at 24 months post-HSCT. MAIT cells have an increased sensibility to common immunosuppressive drugs, which maybe could explain their hampered reconstitution after HSCT

The transcriptome-wide landscape of molecular subtype-specific mRNA expression profiles in acute myeloid leukemia

Molecular classification of acute myeloid leukemia (AML) aids prognostic stratification and clinical management. Our aim in this study is to identify transcriptome-wide mRNAs that are specific to each of the molecular subtypes of AML. We analyzed RNA-sequencing data of 955 AML samples from three cohorts, including the BeatAML project, the Cancer Genome Atlas, and a cohort of Swedish patients to provide a comprehensive transcriptome-wide view of subtype-specific mRNA expression. We identified 729 subtype-specific mRNAs, discovered in the BeatAML project and validated in the other two cohorts. Using unique proteomics data, we also validated the presence of subtype-specific mRNAs at the protein level, yielding a rich collection of potential protein-based biomarkers for the AML community. To enable the exploration of subtype-specific mRNA expression by the broader scientific community, we provide an interactive resource to the public.Peer reviewe

Novel precision medicine approaches and treatment strategies in hematological malignancies

Genetic testing has been applied for decades in clinical routine diagnostics of hematological malignancies to improve disease (sub)classification, prognostication, patient management, and survival. In recent classifications of hematological malignancies, disease subtypes are defined by key recurrent genetic alterations detected by conventional methods (i.e., cytogenetics, fluorescence in situ hybridization, and targeted sequencing). Hematological malignancies were also one of the first disease areas in which targeted therapies were introduced, the prime example being BCR::ABL1 inhibitors, followed by an increasing number of targeted inhibitors hitting the Achilles’ heel of each disease, resulting in a clear patient benefit. Owing to the technical advances in high-throughput sequencing, we can now apply broad genomic tests, including comprehensive gene panels or whole-genome and whole-transcriptome sequencing, to identify clinically important diagnostic, prognostic, and predictive markers. In this review, we give examples of how precision diagnostics has been implemented to guide treatment selection and improve survival in myeloid (myelodysplastic syndromes and acute myeloid leukemia) and lymphoid malignancies (acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia). We discuss the relevance and potential of monitoring measurable residual disease using ultra-sensitive techniques to assess therapy response and detect early relapses. Finally, we bring up the promising avenue of functional precision medicine, combining ex vivo drug screening with various omics technologies, to provide novel treatment options for patients with advanced disease. Although we are only in the beginning of the field of precision hematology, we foresee rapid development with new types of diagnostics and treatment strategies becoming available to the benefit of our patients