Linked Life Data

17082611

Source:http://linkedlifedata.com/resource/pubmed/id/17082611

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
2006-11-3
pubmed:abstractText
A single intratumoral injection of IL-12 and GM-CSF-loaded slow-release microspheres induces T cell-dependent eradication of established primary and metastatic tumors in a murine lung tumor model. To determine how the delivery of cytokines directly to the microenvironment of a tumor nodule induces local and systemic antitumor T cell activity, we characterized therapy-induced phenotypic and functional changes in tumor-infiltrating T cell populations. Analysis of pretherapy tumors demonstrated that advanced primary tumors were infiltrated by CD4+ and CD8+ T cells with an effector/memory phenotype and CD4+CD25+Foxp3+ T suppressor cells. Tumor-associated effector memory CD8+ T cells displayed impaired cytotoxic function, whereas CD4+CD25+Foxp3+ cells effectively inhibited T cell proliferation demonstrating functional integrity. IL-12/GM-CSF treatment promoted a rapid up-regulation of CD43 and CD69 on CD8+ effector/memory T cells, augmented their ability to produce IFN-gamma, and restored granzyme B expression. Importantly, treatment also induced a concomitant and progressive loss of T suppressors from the tumor. Further analysis established that activation of pre-existing effector memory T cells was short-lived and that both the effector/memory and the suppressor T cells became apoptotic within 4 days of treatment. Apoptotic death of pre-existing effector/memory and suppressor T cells was followed by infiltration of the tumor with activated, nonapoptotic CD8+ effector T lymphocytes on day 7 posttherapy. Both CD8+ T cell activation and T suppressor cell purge were mediated primarily by IL-12 and required IFN-gamma. This study provides important insight into how local IL-12 therapy alters the immunosuppressive tumor milieu to one that is immunologically active, ultimately resulting in tumor regression.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0022-1767
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
177
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
6962-73
pubmed:dateRevised
2007-12-3
pubmed:meshHeading
pubmed-meshheading:17082611-Adenocarcinoma, Bronchiolo-Alveolar, pubmed-meshheading:17082611-Animals, pubmed-meshheading:17082611-Apoptosis, pubmed-meshheading:17082611-CD8-Positive T-Lymphocytes, pubmed-meshheading:17082611-Cancer Vaccines, pubmed-meshheading:17082611-Cell Death, pubmed-meshheading:17082611-Cell Line, Tumor, pubmed-meshheading:17082611-Cell Movement, pubmed-meshheading:17082611-Cells, Cultured, pubmed-meshheading:17082611-Female, pubmed-meshheading:17082611-Granulocyte-Macrophage Colony-Stimulating Factor, pubmed-meshheading:17082611-Immunologic Memory, pubmed-meshheading:17082611-Injections, Intralesional, pubmed-meshheading:17082611-Interleukin-12, pubmed-meshheading:17082611-Interleukin-2 Receptor alpha Subunit, pubmed-meshheading:17082611-Lung Neoplasms, pubmed-meshheading:17082611-Lymphocyte Activation, pubmed-meshheading:17082611-Lymphocytes, Tumor-Infiltrating, pubmed-meshheading:17082611-Mice, pubmed-meshheading:17082611-Mice, Inbred BALB C, pubmed-meshheading:17082611-Mice, Knockout, pubmed-meshheading:17082611-Microspheres, pubmed-meshheading:17082611-T-Lymphocytes, Regulatory
pubmed:year
2006
pubmed:articleTitle
Reversing tumor immune suppression with intratumoral IL-12: activation of tumor-associated T effector/memory cells, induction of T suppressor apoptosis, and infiltration of CD8+ T effectors.
pubmed:affiliation
J.G. Brown Cancer Center, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural