ArticleCancer research2013
Durable adoptive immunotherapy for leukemia produced by manipulation of multiple regulatory pathways of CD8+ T-cell tolerance.
Article in Cancer research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed.
- Dysfunction and regulatory interplay of T and B cells in chronic hepatitis B: immunotherapy and emerging antiviral strategies.Frontiers in cellular and infection microbiology · 2024Review
- Fructose Promotes Cytoprotection in Melanoma Tumors and Resistance to Immunotherapy.Cancer immunology research · 2021Article
- γδ T Cells for Leukemia Immunotherapy: New and Expanding Trends.Frontiers in immunology · 2021Review
- Checkpoint blockade immunotherapy enhances the frequency and effector function of murine tumor-infiltrating T cells but does not alter TCRβ diversity.Cancer immunology, immunotherapy : CII · 2019Article
- The Interplay Between the Genetic and Immune Landscapes of AML: Mechanisms and Implications for Risk Stratification and Therapy.Frontiers in oncology · 2019Review
- Chemotherapy-Induced Tumor Cell Death at the Crossroads Between Immunogenicity and Immunotolerance: Focus on Acute Myeloid Leukemia.Frontiers in oncology · 2019Review
- TSC2-deficient tumors have evidence of T cell exhaustion and respond to anti-PD-1/anti-CTLA-4 immunotherapy.JCI insight · 2018Article
- The emerging role of immune checkpoint based approaches in AML and MDS.Leukemia & lymphoma · 2018Review
- Immune-checkpoint inhibitors for combating T-cell dysfunction in cancer.OncoTargets and therapy · 2018Review
- Mechanisms of Immune Tolerance in Leukemia and Lymphoma.Trends in immunology · 2017Review
- Review
- Rescue of Tolerant CD8+ T Cells during Cancer Immunotherapy with IL2:Antibody Complexes.Cancer immunology research · 2016Article
- Improving Adoptive T Cell Therapy: The Particular Role of T Cell Costimulation, Cytokines, and Post-Transfer Vaccination.Frontiers in immunology · 2016Review
- A high-throughput RNAi screen for detection of immune-checkpoint molecules that mediate tumor resistance to cytotoxic T lymphocytes.EMBO molecular medicine · 2015Article
- Checkpoint blockade immunotherapy relies on T-bet but not Eomes to induce effector function in tumor-infiltrating CD8+ T cells.Cancer immunology research · 2015Article
- Programmed death-1 checkpoint blockade in acute myeloid leukemia.Expert opinion on biological therapy · 2015Review
- Blockade of PD-1/PD-L1 promotes adoptive T-cell immunotherapy in a tolerogenic environment.PloS one · 2015Article
- Combined immune checkpoint protein blockade and low dose whole body irradiation as immunotherapy for myeloma.Journal for immunotherapy of cancer · 2015Article
- Inflammation programs self-reactive CD8+ T cells to acquire T-box-mediated effector function but does not prevent deletional tolerance.Journal of leukocyte biology · 2014Article
- Tolerance and exhaustion: defining mechanisms of T cell dysfunction.Trends in immunology · 2014Review
Corrections and comments
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Authors and funding
9 authors.
Funding
Abstract
Tolerizing mechanisms within the host and tumor microenvironment inhibit T-cell effector functions that can control cancer. These mechanisms blunt adoptive immunotherapy with infused T-cells due to a complex array of signals that determine T-cell tolerance, survival, or deletion. Ligation of the negative regulatory receptors CTLA4, PD-1(PDCD1), or LAG3 on T-cells normally hinders their response to antigen through nonredundant biochemical processes that interfere with stimulatory pathways. In this study, we used an established mouse model of T-cell tolerance to define the roles of these inhibitory receptors in regulating CD8(+) T-cell tolerance during adoptive immunotherapy to treat leukemia. Blocking CTLA4 and PD-1 in vivo combined to promote survival of transferred T-cells despite powerful deletional signals that mediate Bim (BCL2L11)-dependent apoptosis. However, this dual blockade was not optimal for stimulating effector function by responding T-cells, which required the additional blockade of LAG3 to induce full expansion and allow the acquisition of robust cytolytic activity. Thus, the cooperation of multiple distinct regulatory pathways was needed for the survival and effector differentiation of adoptively transferred tumor-reactive CD8(+) T-cells. Our work defines the immune escape pathways in which simultaneous blockade could yield durable immunotherapeutic responses that can eradicate disseminated leukemia.
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Registered trials
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