Cooperation between molecular targets of costimulation in promoting T cell persistence and tumor regression

Costimulation regulates multiple cellular processes of T cells inducing proliferation, expansion, and survival. The molecular targets of costimulation might then be useful to augment T cell activities. Two defined targets of costimulatory signals in primary T cells are the anti-apoptotic bcl-2 family molecule Bcl-x_L, and survivin, an inhibitor of apoptosis family member that might regulate both cell division and survival. However, the relative importance of, and relationship between, these molecules in primary T cells is not clear. To understand whether they have overlapping or cooperative functions, we used retrovirus-mediated transduction to introduce Bcl-x _L and survivin separately, or together linked by a 2A picornavirus self-cleaving peptide, into Agresponding CD8⁺ T cells. We found that CD8⁺ effector T cells expressing both Bcl-x_L and survivin strongly expanded at an early stage and had a long-term survival advantage over cells transduced with either molecule alone. In vivo, with response to tumorexpressed Ag following adoptive T cell transfer, Ag-reactive CD8 ⁺ T cells expressing both Bcl-x_L and survivin displayed greatly enhanced tumor protective activity compared with CD8⁺ T cells expressing either molecule introduced separately. These results indicate that Bcl-x_L and survivin can critically contribute in a cooperative, nonredundant manner to augment the accumulation and persistence of CD8 ⁺ T cells following encounter with Ag. The data provide new insights into why costimulatory signals might need to be sustained over time and suggest a potential novel approach to augment cellular immunotherapy for cancer.