The Multifaceted Role of Th17 Lymphocytes and Their Associated Cytokines in Cancer

While the role of T helper 17 lymphocytes (Th17) in the pathogenesis of autoimmune diseases and in infectious immunity has been relatively well defined, the impact of these cells and their associated cytokines on cancer development is still under debate. Although multiple reports have indicated that Th17 can promote anticancer immunity, others have argued that these cells may exhibit tumor-promoting properties. This dichotomy in the function of Th17 lymphocytes in cancer may be related to the versatile nature of these cells, being capable of differentiating into either proinflammatory Th1 or suppressive FoxP3-expressing Treg cells or hybrid T cell subsets depending on the underlying environmental conditions. In the current review, we examine the role of Th17 lymphocytes and Th17-associated cytokines in cancer and discuss how factors that control their final lineage commitment decision may influence the balance between their tumor-promoting versus tumor-suppressing properties

Cytotoxic and antigen presenting functions of T helper-1-activated dendritic cells

Although primarily defined by their cardinal antigen-presenting function, dendritic cells (DCs) are also equipped with cytotoxic properties. We have recently reported that DCs activated by IFNγ-secreting Th-1 lymphocytes can kill cancer cells and subsequently present the acquired tumor-derived antigens to T lymphocytes both in vitro and in vivo

Has the shortage of fludarabine altered the current paradigm of lymphodepletion in favor of bendamustine?

The most common lymphodepletion regimen used prior to infusion of chimeric antigen receptor-T cells (CAR-T) is cyclophosphamide (CY) in combination with fludarabine (Flu) (CY-FLU). While cyclophosphamide (CY) possesses lymphotoxic effects, it concurrently preserves regulatory T cell activity, potentially affecting the efficacy of CAR-T cells. Moreover, the use of fludarabine (FLU) has been linked to neurotoxicity, which could complicate the early detection of immune effector cell-associated neurotoxicity syndrome (ICANS) observed in CAR-T cell therapy. Given the ongoing shortage of FLU, alternative lymphodepleting agents have become necessary. To date, only a limited number of studies have directly compared different lymphodepleting regimens, and most of these comparisons have been retrospective in nature. Herein, we review the current literature on lymphodepletion preceding CAR-T cell therapies for lymphoid hematologic malignancies, with a specific focus on the use of bendamustine (BEN). Recent evidence suggests that administering BEN before CAR-T cell infusion yields comparable efficacy, possibly with a more favorable toxicity profile when compared to CY-FLU. This warrants further investigation through randomized prospective studies

The Dendritic Cell-Regulatory T Lymphocyte Crosstalk Contributes to Tumor-Induced Tolerance

Tumor cells commonly escape from elimination by innate and adaptive immune responses using multiple strategies among which is the active suppression of effector immune cells. Regulatory T lymphocytes (Treg) and tolerogenic dendritic cells play essential roles in the establishment and persistence of cancer-induced immunosuppression. Differentiating dendritic cells (DCs) exposed to tumor-derived factors may be arrested at an immature stage becoming inept at initiating immune responses and may induce effector T-cell anergy or deletion. These tolerogenic DCs, which accumulate in patients with different types of cancers, are also involved in the generation of Treg. In turn, Treg that expand during tumor progression contribute to the immune tolerance of cancer by impeding DCs' ability to orchestrate immune responses and by directly inhibiting antitumoral T lymphocytes. Herein we review these bidirectional communications between DCs and Treg as they relate to the promotion of cancer-induced tolerance

Evidence for a Novel, Caspase-8-Independent, Fas Death Domain-Mediated Apoptotic Pathway

Certain caspase-8 null cell lines demonstrate resistance to Fas-induced apoptosis, indicating that the Fas/FasL apoptotic pathway may be caspase-8-dependent. Some reports, however, have shown that Fas induces cell death independent of caspase-8. Here we provide evidence for an alternative, caspase-8-independent, Fas death domain-mediated apoptotic pathway. Murine 12B1-D1 cells express procaspase-3, -8, and -9, which were activated upon the dimerization of Fas death domain. Bid was cleaved and mitochondrial transmembrane potential was disrupted in this apoptotic process. All apoptotic events were completely blocked by the broad-spectrum caspase inhibitor Z-VAD-FMK, but not by other peptide caspase inhibitors. Cyclosporin A (CsA), which inhibits mitochondrial transition pore permeability, blocked neither pore permeability disruption nor caspase activation. However, CsA plus caspase-8 inhibitor blocked all apoptotic events of 12B1-D1 induced by Fas death domain dimerization. Our data therefore suggest that there is a novel, caspase-8-independent, Z-VAD-FMK-inhibitable, apoptotic pathway in 12B1-D1 cells that targets mitochondria directly

Human lymphocytes mobilized with exercise have an anti-tumor transcriptomic profile and exert enhanced graft-versus-leukemia effects in xenogeneic mice

BackgroundEvery bout of exercise mobilizes and redistributes large numbers of effector lymphocytes with a cytotoxic and tissue migration phenotype. The frequent redistribution of these cells is purported to increase immune surveillance and play a mechanistic role in reducing cancer risk and slowing tumor progression in physically active cancer survivors. Our aim was to provide the first detailed single cell transcriptomic analysis of exercise-mobilized lymphocytes and test their effectiveness as a donor lymphocyte infusion (DLI) in xenogeneic mice engrafted with human leukemia.MethodsPeripheral blood mononuclear cells (PBMCs) were collected from healthy volunteers at rest and at the end of an acute bout of cycling exercise. Flow cytometry and single-cell RNA sequencing was performed to identify phenotypic and transcriptomic differences between resting and exercise-mobilized cells using a targeted gene expression panel curated for human immunology. PBMCs were injected into the tail vein of xenogeneic NSG-IL-15 mice and subsequently challenged with a luciferase tagged chronic myelogenous leukemia cell line (K562). Tumor growth (bioluminescence) and xenogeneic graft-versus-host disease (GvHD) were monitored bi-weekly for 40-days.ResultsExercise preferentially mobilized NK-cell, CD8+ T-cell and monocyte subtypes with a differentiated and effector phenotype, without significantly mobilizing CD4+ regulatory T-cells. Mobilized effector lymphocytes, particularly effector-memory CD8+ T-cells and NK-cells, displayed differentially expressed genes and enriched gene sets associated with anti-tumor activity, including cytotoxicity, migration/chemotaxis, antigen binding, cytokine responsiveness and alloreactivity (e.g. graft-versus-host/leukemia). Mice receiving exercise-mobilized PBMCs had lower tumor burden and higher overall survival (4.14E+08 photons/s and 47%, respectively) at day 40 compared to mice receiving resting PBMCs (12.1E+08 photons/s and 22%, respectively) from the same donors (p<0.05). Human immune cell engraftment was similar for resting and exercise-mobilized DLI. However, when compared to non-tumor bearing mice, K562 increased the expansion of NK-cell and CD3+/CD4-/CD8- T-cells in mice receiving exercise-mobilized but not resting lymphocytes, 1-2 weeks after DLI. No differences in GvHD or GvHD-free survival was observed between groups either with or without K562 challenge.ConclusionExercise in humans mobilizes effector lymphocytes with an anti-tumor transcriptomic profile and their use as DLI extends survival and enhances the graft-versus-leukemia (GvL) effect without exacerbating GvHD in human leukemia bearing xenogeneic mice. Exercise may serve as an effective and economical adjuvant to increase the GvL effects of allogeneic cell therapies without intensifying GvHD

Cytotoxic dendritic cells generated from cancer patients.

International audienceKnown for years as professional APCs, dendritic cells (DCs) are also endowed with tumoricidal activity. This dual role of DC as killers and messengers may have important implications for tumor immunotherapy. However, the tumoricidal activity of DCs has mainly been investigated in animal models. Cancer cells inhibit antitumor immune responses using numerous mechanisms, including the induction of immunosuppressive/ tolerogenic DCs that have lost their ability to present Ags in an immunogenic manner. In this study, we evaluated the possibility of generating tumor killer DCs from patients with advanced-stage cancers. We demonstrate that human monocyte-derived DCs are endowed with significant cytotoxic activity against tumor cells following activation with LPS. The mechanism of DC-mediated tumor cell killing primarily involves peroxynitrites. This observed cytotoxic activity is restricted to immature DCs. Additionally, after killing, these cytotoxic DCs are able to activate tumor Ag-specific T cells. These observations may open important new perspectives for the use of autologous cytotoxic DCs in cancer immunotherapy strategies

COVID-19 vaccination produces exercise-responsive SARS-CoV-2-specific T-cells regardless of infection history

Purpose: The mobilization and redistribution of severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) specific T-cells and neutralizing antibodies during exercise is purported to increase immune surveillance and protect against severe coronavirus disease 2019 (COVID-19). We sought to determine if COVID-19 vaccination would elicit exercise-responsive SARS-CoV-2 T-cells and transiently alter neutralizing antibody titers. Methods: 18 healthy participants completed a 20 min bout of graded cycling exercise before and/or after receiving a COVID-19 vaccine. All major leukocyte subtypes were enumerated before, during, and after exercise by flow cytometry, and immune responses to SARS CoV-2 were determined using whole blood peptide stimulation assays, T-cell receptor (TCR) sequencing, and SARS-CoV-2 neutralizing antibody serology. Results: COVID-19 vaccination had no effect on the mobilization or egress of major leukocyte subsets in response to intensity-controlled graded exercise. However, noninfected participants had a significantly reduced mobilization of CD4+ and CD8+ naive T-cells, as well as CD4+ central memory T-cells, after vaccination (synthetic immunity group); this was not seen after vaccination in those with prior SARS CoV-2 infection (hybrid immunity group). Acute exercise after vaccination robustly mobilized SARSCoV-2 specific T-cells to blood in an intensity-dependent manner. Both groups mobilized T-cells that reacted to spike protein; however, only the hybrid immunity group mobilized T-cells that reacted to membrane and nucleocapsid antigens. Neutralizing antibodies increased significantly during exercise only in the hybrid immunity group. Conclusion: These data indicate that acute exercise mobilizes SARS CoV-2-specific Tcells that recognize spike protein and increases the redistribution of neutralizing antibodies in individuals with hybrid immunity

Allogeneic haematopoietic cell transplantation for extranodal natural killer/Tâ cell lymphoma, nasal type: a CIBMTR analysis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146342/1/bjh14879.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146342/2/bjh14879_am.pd

Transfusion independence after repeated haploidentical hematopoietic cell transplants in a patient with congenital dyserythropoietic anemia type II and hemosiderosis

Matched related or unrelated donor allogeneic HCT has occasionally been applied in patients with severe CDA type II and proven to be curative. We report on the first patient with CDA to undergo haploidentical bone marrow transplantation with PT-CY. A 12-year-old boy with severe hemosiderosis, and a, consequently, disturbed BM microenvironment, developed recurrent graft failures and required salvage with two additional haploidentical HCTs. He achieved complete donor chimerism and transfusion independence after the third HCT. Our case underscores the risks associated with performing haploidentical HCT in older pediatric patients with CDA and severe chronic iron overload.12 month embargo; published online: 17 September 2019This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]