Bortezomib enhances cytotoxicity of ex vivo-expanded gamma delta T cells against acute myeloid leukemia and T-cell acute lymphoblastic leukemia

Story, Jamie Y.; Zoine, Jaquelyn T.; Burnham, Rebecca E.; Hamilton, Jamie A.G.; Spencer, H. Trent; Doering, Christopher B.; Raikar, Sunil S.

doi:10.1016/j.jcyt.2020.09.010

Cited by 20 publications

(23 citation statements)

References 43 publications

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“…Tumors can be conditioned for γδ T cell recognition through agents that upregulate tumor phosphoantigens 19 , 48 , 49 or stress antigens. 50–54 Alternatively, there is ample opportunity to engineer γδ T lymphocytes to traffic toward solid tumors through CAR expression. 55–58 …”

Section: Discussionmentioning

confidence: 99%

Dissecting the cellular components of ex vivo γδ T cell expansions to optimize selection of potent cell therapy donors for neuroblastoma immunotherapy trials

Jonus

Burnham

et al. 2022

OncoImmunology

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γδ T lymphocytes represent an emerging class of cellular immunotherapy with preclinical promise to treat cancer, notably neuroblastoma. The innate-like immune cell subset demonstrates inherent cytoxicity toward tumor cells independent of MHC recognition, enabling allogeneic administration of healthy donor-derived γδ T cell therapies. A current limitation is the substantial interindividual γδ T cell expansion variation among leukocyte collections. Overcoming this limitation will enable realization of the full potential of allogeneic γδ T-based cellular therapy. Here, we characterize γδ T cell expansions from healthy adult donors and observe that highly potent natural killer (NK) lymphocytes expand with γδ T cells under zoledronate and IL-2 stimulation. The presence of NK cells correlates with both the expansion potential of γδ T cells and the overall potency of the γδ T cell therapy. However, the potency of the cell therapy in combination with an antibody-based immunotherapeutic, dinutuximab, appears to be independent of γδ T/NK cell content both in vitro and in vivo , which minimizes the implication of interindividual expansion differences toward efficacy. Collectively, these studies highlight the utility of maintaining the NK cell population within expanded γδ T cell therapies and suggest a synergistic action of combined innate cell immunotherapy toward neuroblastoma.

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Section: Discussionmentioning

confidence: 99%

Dissecting the cellular components of ex vivo γδ T cell expansions to optimize selection of potent cell therapy donors for neuroblastoma immunotherapy trials

Jonus

Burnham

et al. 2022

OncoImmunology

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“…Bortezomib combined with artesunate has obvious synergistic effects on the proliferation, apoptosis, and autophagy of MV4-11 cell lines, which may be associated with the expression of Bcl-2 family proteins. The treatment of human leukemia HL60 xenografts using Bortezomib and ATRA not only increased the differentiation, but also inhibited tumor growth ( Ying et al, 2013 ; Hu et al, 2019 ; Moore et al, 2020 ; Story et al, 2021 ). Bryostatin-1 notably inhibited cell proliferation and induced NB4 cell differentiation into monocytes/macrophages.…”

Section: Discussionmentioning

confidence: 99%

The Multi-Omic Prognostic Model of Oxidative Stress-Related Genes in Acute Myeloid Leukemia

Dong

Zhang

2021

Front. Genet.

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Background: Acute myeloid leukemia (AML) is one of the most common cancers in the world, and oxidative stress is closely related to leukemia. A lot of effort has been made to improve the prognosis of AML. However, the situation remains serious. Hence, we focused on the study of prognostic genes in AML.Materials and Methods: Prognostic oxidative stress genes were screened out. The gene expression profile of AML patients was downloaded from the The Cancer Genome Atlas (TCGA) database. The oxidative stress-related model was constructed, by which the prognosis of AML patients was predicted using the two GEO GSE23143 datasets and the stability of the GSE71014 authentication model.Results: The prognostic oxidative stress genes were screened out in AML, and the prognostic genes were significantly enriched in a large number of pathways based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. There was a complex interaction between prognostic genes and transcription factors. After constructing the prediction model, the clinical predictive value of the model was discussed in a multi-omic study. We investigated the sensitivity of risk score to common chemotherapeutic agents, the influence of signaling pathways on the prognosis of AML patients, and the correlation of multiple genes with immune score and immune dysfunction.Conclusions: A highly effective prognostic risk model for AML patients was established and validated. The association of prognostic oxidative stress genes with drug sensitivity, signaling pathways, and immune infiltration was explored. The results suggested that oxidative stress genes promised to be potential prognostic biomarkers for AML, which may provide a new basis for disease management.

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“…Reports indicate that a new type of allo-human leukocyte antigen (HLA)-restricted and CD8α-dependent Vγ5Vδ1 TCR has been identified, and the classic anti-HLA-directed γδ TCR-mediated immune response can selectively act on blood and solid tumor cells in vivo and in vitro [83]. Bortezomib can significantly increase the expression of ULBP proteins in acute myeloid leukemia cells, thereby enhancing the killing of tumor cells by γδ T cells [84]. Vδ1T cells are known to recognize CD1c in the absence of specific foreign antigens, and CD1-restricted γδ T cells can mediate the maturation of dendritic cells for tumor antigen presentation [85].…”

Section: Therapeutic Opportunities Brought By Tumor-associated Protei...mentioning

confidence: 99%

Tumor-associated protein ligands recognized by human γδ T cell receptor and their implications in cancer therapy

Liu

Zhang

et al. 2022

Explor Immunol

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In recent years, immunologists have been working to utilize the functional mechanism of the immune system to research new tumor treatment methods and achieved a major breakthrough in 2013, which was listed as one of the top 10 scientific breakthroughs of 2013 by Science magazine (see “Cancer immunotherapy”. Science. 2013;342:1417. doi: 10.1126/science.1249481). Currently, two main methods are used in clinical tumor immunotherapy: immune checkpoint inhibitors and chimeric antigen receptor (CAR) T cells. Clinical responses to checkpoint inhibitors rely on blockade of the target neoantigens expressed on the surfaces of tumor cells, which can inhibit T cell activity and prevent the T cell immune response; therefore, the therapeutic effect is limited by the tumor antigen expression level. While CAR-T cell therapy can partly enhance neoantigen recognition of T cells, problems remain in the current treatment for solid tumors, such as restricted transport of adoptively transferred cells to the tumor site and off-targets. Immunologists have therefore turned their attention to γδ T cells, which are not restricted by the major histocompatibility complex (MHC) for neoantigen recognition and are able to initiate a rapid immune response at an early stage. However, due to the lack of an understanding of the antigens that γδ T cells recognize, the role of γδ T cells in tumorigenesis and tumor development is not clearly understood. In the past few years, extensive data identifying antigen ligands recognized by γδ T cells have been obtained, mainly focusing on bisphosphonates and small-molecule polypeptides, but few studies have focused on protein ligands recognized by γδ T cells. In this paper, it is reviewed and analyzed that the tumor-associated protein ligands of γδ T cells that have been discovered thus far, hoping to provide new ideas for the comprehensive application of γδ T cells in tumor immunotherapy.

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Bortezomib enhances cytotoxicity of ex vivo-expanded gamma delta T cells against acute myeloid leukemia and T-cell acute lymphoblastic leukemia

Cited by 20 publications

References 43 publications

Dissecting the cellular components of ex vivo γδ T cell expansions to optimize selection of potent cell therapy donors for neuroblastoma immunotherapy trials

Dissecting the cellular components of ex vivo γδ T cell expansions to optimize selection of potent cell therapy donors for neuroblastoma immunotherapy trials

The Multi-Omic Prognostic Model of Oxidative Stress-Related Genes in Acute Myeloid Leukemia

Tumor-associated protein ligands recognized by human γδ T cell receptor and their implications in cancer therapy

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