Document Detail


Durable adoptive immunotherapy for leukemia produced by manipulation of multiple regulatory pathways of CD8+ T-cell tolerance.
MedLine Citation:
PMID:  23188506     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Melissa M Berrien-Elliott; Stephanie R Jackson; Jennifer M Meyer; Craig J Rouskey; Thanh-Long M Nguyen; Hideo Yagita; Philip D Greenberg; Richard J DiPaolo; Ryan M Teague
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-11-27
Journal Detail:
Title:  Cancer research     Volume:  73     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-18     Completed Date:  2013-03-26     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  605-16     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD / metabolism
CD8-Positive T-Lymphocytes / immunology*
CTLA-4 Antigen / antagonists & inhibitors
Cell Differentiation
Cell Line, Tumor
Immune Tolerance*
Immunotherapy, Adoptive*
Mice
Mice, Transgenic
Programmed Cell Death 1 Receptor / antagonists & inhibitors
Tumor Escape*
Grant Support
ID/Acronym/Agency:
CA33084/CA/NCI NIH HHS; R01 AI087764/AI/NIAID NIH HHS; R01 CA033084/CA/NCI NIH HHS; R01AI087764/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD; 0/CD223 antigen; 0/CTLA-4 Antigen; 0/Ctla4 protein, mouse; 0/Pdcd1 protein, mouse; 0/Programmed Cell Death 1 Receptor
Comments/Corrections

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