Abrogating Cbl-b in effector CD8(+) T cells improves the efficacy of adoptive therapy of leukemia in mice.
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.
Stromnes
Ingunn M
IM
Department of Immunology, University of Washington, Seattle, Washington 98195-6425, USA.
Blattman
Joseph N
JN
Tan
Xiaoxia
X
Jeevanjee
Sara
S
Gu
Hua
H
Greenberg
Philip D
PD
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D018106:CD28 Antigens / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis / Q000494:pharmacology; D007942:Leukemia, Experimental / Q000628:therapy*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D050721:Proto-Oncogene Proteins c-cbl / Q000037:antagonists & inhibitors / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D018106:CD28 Antigens; C118387:Cblb protein, mouse; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma; D050721:Proto-Oncogene Proteins c-cbl