Vγ9Vδ2 T cells are promising candidates for cellular tumor immunotherapy. Due to their HLA-independent mode of action, allogeneic Vγ9Vδ2 T cells can be considered for clinical application. To apply ...allogeneic Vγ9Vδ2 T cells in adoptive immunotherapy, the methodology used to obtain adequate cell numbers with optimal effector function in vitro needs to be optimized, and clinical safety and efficacy also need to be proven. Therefore, we developed a novel formula to improve the expansion of peripheral γδ T cells from healthy donors. Then, we used a humanized mouse model to validate the therapeutic efficacy of expanded γδ T cells in vivo; furthermore, the expanded γδ T cells were adoptively transferred into late-stage liver and lung cancer patients. We found that the expanded cells possessed significantly improved immune effector functions, including proliferation, differentiation, and cancer cell killing, both in vitro and in the humanized mouse model. Furthermore, a phase I clinical trial in 132 late-stage cancer patients with a total of 414 cell infusions unequivocally validated the clinical safety of allogeneic Vγ9Vδ2 T cells. Among these 132 patients, 8 liver cancer patients and 10 lung cancer patients who received ≥5 cell infusions showed greatly prolonged survival, which preliminarily verified the efficacy of allogeneic Vγ9Vδ2 T-cell therapy. Our clinical studies underscore the safety and efficacy of allogeneic Vγ9Vδ2 T-cell immunotherapy, which will inspire further clinical investigations and eventually benefit cancer patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Pulmonary fibrosis is a chronic progressive lung disease with few treatments. Human mesenchymal stem cells (MSCs) have been shown to be beneficial in pulmonary fibrosis because they have ...immunomodulatory capacity. However, there is no reliable model to test the therapeutic effect of human MSCs in vivo. To mimic pulmonary fibrosis in humans, we established a novel bleomycin-induced pulmonary fibrosis model in humanized mice. With this model, the benefit of human MSCs in pulmonary fibrosis and the underlying mechanisms were investigated. In addition, the relevant parameters in patients with pulmonary fibrosis were examined. We demonstrate that human CD8
T cells were critical for the induction of pulmonary fibrosis in humanized mice. Human MSCs could alleviate pulmonary fibrosis and improve lung function by suppressing bleomycin-induced human T-cell infiltration and proinflammatory cytokine production in the lungs of humanized mice. Importantly, alleviation of pulmonary fibrosis by human MSCs was mediated by the PD-1/programmed death-ligand 1 pathway. Moreover, abnormal PD-1 expression was found in circulating T cells and lung tissues of patients with pulmonary fibrosis. Our study supports the potential benefit of targeting the PD-1/programmed death-ligand 1 pathway in the treatment of pulmonary fibrosis.
Abstract
We present an interim analysis of a registered clinical study (NCT04800133) to establish immunobridging with various antibody and cellular immunity markers and to compare the immunogenicity ...and reactogenicity of 2-dose BNT162b2 and CoronaVac in healthy adolescents as primary objectives. One-dose BNT162b2, recommended in some localities for risk reduction of myocarditis, is also assessed. Antibodies and T cell immune responses are non-inferior or similar in adolescents receiving 2 doses of BNT162b2 (BB,
N
= 116) and CoronaVac (CC,
N
= 123) versus adults after 2 doses of the same vaccine (BB,
N
= 147; CC,
N
= 141) but not in adolescents after 1-dose BNT162b2 (B,
N
= 116). CC induces SARS-CoV-2 N and N C-terminal domain seropositivity in a higher proportion of adolescents than adults. Adverse reactions are mostly mild for both vaccines and more frequent for BNT162b2. We find higher S, neutralising, avidity and Fc receptor-binding antibody responses in adolescents receiving BB than CC, and a similar induction of strong S-specific T cells by the 2 vaccines, in addition to N- and M-specific T cells induced by CoronaVac but not BNT162b2, possibly implying differential durability and cross-variant protection by BNT162b2 and CoronaVac, the 2 most used SARS-CoV-2 vaccines worldwide. Our results support the use of both vaccines in adolescents.
Elevated T cell responses were also found in the mice vaccinated with the S-RBD vaccine. ...the authors further evaluated the involvement of cellular immune response in the prevention of SARS-CoV-2 ...infection 5. Interestingly, adoptive transferring the sera obtained from vaccinated mice effectively protected the recipient mice from live SARS-CoV-2 infection, while the splenic T cells from same vaccinated mice did not show similar protective effect. ...the protection was mainly mediated by the specific humoral responses induced by the S-RBD vaccine. ...the authors determined the safety profile of the S-RBD vaccine 5.
Vγ9Vδ2-T cells are considered as potent effector cells for tumor immunotherapy through directly killing tumor cells and indirectly regulating other innate and adaptive immune cells to establish ...antitumoral immunity. The antitumoral activity of Vγ9Vδ2-T cells is governed by a complicated set of activating and inhibitory cell receptors. In addition, cytokine milieu in tumor microenvironment can also induce the pro-tumoral activities and functional plasticity of Vγ9Vδ2-T cells. Here, we review the anti- versus pro-tumoral activities of Vγ9Vδ2-T cells and discuss the mechanisms underlying the recognition, activation, differentiation and regulation of Vγ9Vδ2-T cells in tumor immunosurveillance. The comprehensive understanding of the dual face of Vγ9Vδ2-T cells in tumor immunology may improve the therapeutic efficacy and clinical outcomes of Vγ9Vδ2-T cell-based tumor immunotherapy.
Background Wiskott-Aldrich syndrome (WAS) is a severe disorder characterized by thrombocytopenia, eczema, immunodeficiency, and increased risk of autoimmune disease and lymphoid malignancies. The ...immunodeficiency caused by a lack of WAS protein expression has been mainly attributed to defective T-cell functions. Whether WAS mutations differentially influence the T-cell receptor (TCR) diversity of different T-cell subsets is unknown. Objective We aimed to identify the degree and pattern of skewing in the variable region of the TCR β-chain (Vβ) in different T-cell subsets from patients with WAS. Methods The TCR repertoire diversity in total peripheral T cells, sorted CD4+ and CD8+ T cells, and CD45RA+ (CD45RA+ CD45RO− cells) and CD45RO+ (CD45RA− CD45RO+ cells) CD4+ and CD8+ T cells from patients with WAS and age-matched healthy control subjects was analyzed and compared by using spectratyping of complementarity-determining region 3. The complementarity-determining region 3 of TCRβ transcripts in CD45RA+ CD4+ and CD45RA+ CD8+ T cells, CD45RO+ CD4+ T cells, CD8+ terminally differentiated effector memory T (Temra) cells, and naive CD8+ T cells (CD8+ CD45RO− CCR7+ cells) from patients and control subjects were analyzed and compared by using high-throughput sequencing. Results The TCR repertoire diversity in CD45RO+ CD4+ T cells and CD8+ Temra cells of patients with WAS was significantly skewed in comparison with that seen in age-matched control subjects. Conclusion Our results indicate that WAS gene mutations selectively influence TCR repertoire development or expansion in CD45RO+ (memory) CD4+ T cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Although γδ-T cell-based tumor immunotherapy using phosphoantigens to boost γδ-T cell immunity has shown success in some cancer patients, the clinical application is limited due to the rapid ...exhaustion of Vγ9Vδ2-T cells caused by repetitive stimulation from phosphoantigens and the profoundly immunosuppressive tumor microenvironment (TME). In this study, using a cell culture medium containing human and viral interleukin-10 (hIL-10 and vIL-10) secreted from EBV-transformed lymphoblastoid B cell lines (EBV-LCL) to mimic the immunosuppressive TEM, we found that the antitumor activity of Vγ9Vδ2-T cells was highly suppressed by endogenous hIL-10 and vIL-10 within the TME. CD137 costimulation could provide an anti-exhaustion signal to mitigate the suppressive effects of IL-10 in TME by suppressing IL-10R1 expression on Vγ9Vδ2-T cells. CD137 costimulation also improved the compromised antitumor activity of Vγ9Vδ2-T cells in TME with high levels of IL-10 in Rag2
-/-
γc
-/-
mice. In humanized mice, CD137 costimulation boosted the therapeutic effects of aminobisphosphonate pamidronate against EBV-induced lymphoma. Our study offers a novel approach to overcoming the obstacle of the hIL-10 and vIL-10-mediated immunosuppressive microenvironment by costimulating CD137 and enhancing the efficacy of γδ-T cell-based tumor therapy.
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