Permissive Expansion And Homing Of Adoptively Transferred T Cells In Tumor-Bearing Hosts

Activated T cells expressing endogenous or transduced TCRs are two cell types currently used in clinical adoptive T-cell therapy. The ability of these cells to recognize their antigen, expand and traffic to the tumor site are the initial steps necessary for successful therapy. In this study, we used in vivo bioluminescent imaging (BLI) of Renilla luciferase (RLuc) expressing T cells to evaluate the ability of adoptively transferred T cells to survive, expand and home to tumor site in vivo. Using this method, termed RT-Rack (Rluc T cell tracking), we followed T-cell response against tumors in vivo. Expansion and homing of adoptively transferred T cells were antigen dependent, but independent of the host immune status. Moreover, we successfully detected T-cell response to small and large tumors, including autochthonous liver tumors. The adoptively transferred T cells were not ignorant or excluded in a partially tolerant host, which expressed low level of the target in the periphery. Using T cell receptor (TCR)-engineered T cells, we showed the ability of these cells to respond in tumor-bearing hosts by expanding and homing to the tumor site. In all these models, the host immune status, the nature of the tumor or of the antigen, the tumor size and the presence of the targeted antigen in the periphery did not prevent the adoptively transferred T cells from responding by expanding and homing to the tumor. However, T cells had higher expression of the inhibitory receptor PD1 and reduced functional activity when a self-antigen was targeted.What's new? For adoptive T-cell therapy (ATCT) to work, tumor-specific T cells must divide and home in the tumors after transfer into the host. In this study, the authors developed an imaging technique to observe these cells over time, in vivo. Surprisingly, the rate-limiting step for anti-tumor activity doesn't appear to be the survival, target recognition, proliferation or homing of the adoptively transferred T cells. Rather, it may be the ability of these cells to differentiate fully into effector T cells expressing low levels of the inhibitory receptor PD1 that determines the efficacy of ATCT.