RGD Reference Report - Abrogating Cbl-b in effector CD8(+) T cells improves the efficacy of adoptive therapy of leukemia in mice. - Rat Genome Database

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Abrogating Cbl-b in effector CD8(+) T cells improves the efficacy of adoptive therapy of leukemia in mice.

Authors: Stromnes, IM  Blattman, JN  Tan, X  Jeevanjee, S  Gu, H  Greenberg, PD 
Citation: Stromnes IM, etal., J Clin Invest. 2010 Oct;120(10):3722-34. doi: 10.1172/JCI41991. Epub 2010 Sep 20.
RGD ID: 11038805
Pubmed: PMID:20890046   (View Abstract at PubMed)
PMCID: PMC2947221   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI41991   (Journal Full-text)

The clinical use of adoptive immunotherapy with tumor-reactive T cells to treat established cancers is limited in part by the poor in vivo survival and function of the transferred T cells. Although administration of exogenous cytokines such as IL-2 can promote T cell survival, such strategies have many nonspecific activities and are often associated with toxicity. We show here that abrogating expression of Casitas B-lineage lymphoma b (Cbl-b), a negative regulator of lymphocyte activation, in tumor-reactive CD8(+) T cells expanded ex vivo increased the efficacy of adoptive immunotherapy of disseminated leukemia in mice. Mechanistically, Cbl-b abrogation bypassed the requirement for exogenous IL-2 administration for tumor eradication in vivo. In addition, CD8(+) T cells lacking Cbl-b demonstrated a lower threshold for activation, better survival following target recognition and stimulation, and enhanced proliferative responses as a result of both IL-2-dependent and -independent pathways. Importantly, siRNA knockdown of Cbl-b in human CD8(+)CD28- effector T cell clones similarly restored IL-2 production and proliferation following target recognition independent of exogenous IL-2, enhanced IFN-gamma production, and increased target avidity. Thus, abrogating Cbl-b expression in effector T cells may improve the efficacy of adoptive therapy of some human malignancies.




  
Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
CBLHumanExperimental Leukemia treatmentISOCbl (Mus musculus) RGD 
CblMouseExperimental Leukemia treatmentIMP  RGD 
CblRatExperimental Leukemia treatmentISOCbl (Mus musculus) RGD 


Genes (Rattus norvegicus)
Cbl  (Cbl proto-oncogene)

Genes (Mus musculus)
Cbl  (Casitas B-lineage lymphoma)

Genes (Homo sapiens)
CBL  (Cbl proto-oncogene)