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

Publication Type:

Journal Article

Source:

The Journal of clinical investigation, Volume 120, Issue 10, p.3722-34 (2010)

Keywords:

2010, Adaptor Proteins, Signal Transducing, Animals, Antigens, CD28, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Center-Authored Paper, Clinical Research Division, Immunotherapy, Adoptive, interferon-gamma, Interleukin-2, Leukemia, Experimental, Lymphocyte Activation, MICE, Mice, Inbred C57BL, Proto-Oncogene Proteins c-cbl, Receptors, Antigen, T-Cell

Abstract:

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-γ 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.