[HTML][HTML] Two-photon imaging of intratumoral CD8+ T cell cytotoxic activity during adoptive T cell therapy in mice

B Breart, F Lemaître, S Celli… - The Journal of clinical …, 2008 - Am Soc Clin Investig
B Breart, F Lemaître, S Celli, P Bousso
The Journal of clinical investigation, 2008Am Soc Clin Investig
CTLs have the potential to attack tumors, and adoptive transfer of CTLs can lead to tumor
regression in mouse models and human clinical settings. However, the dynamics of tumor
cell elimination during efficient T cell therapy is unknown, and it is unclear whether CTLs act
directly by destroying tumor cells or indirectly by initiating the recruitment of innate immune
cells that mediate tumor damage. To address these questions, we report real-time imaging
of tumor cell apoptosis in vivo using intravital 2-photon microscopy and a Förster resonance …
CTLs have the potential to attack tumors, and adoptive transfer of CTLs can lead to tumor regression in mouse models and human clinical settings. However, the dynamics of tumor cell elimination during efficient T cell therapy is unknown, and it is unclear whether CTLs act directly by destroying tumor cells or indirectly by initiating the recruitment of innate immune cells that mediate tumor damage. To address these questions, we report real-time imaging of tumor cell apoptosis in vivo using intravital 2-photon microscopy and a Förster resonance energy transfer–based (FRET-based) reporter of caspase 3 activity. In a mouse model of solid tumor, we found that tumor regression after transfer of in vitro–activated CTLs occurred primarily through the direct action of CTLs on each individual tumor cell, with a minimal bystander effect. Surprisingly, the killing of 1 target cell by an individual CTL took an extended period of time, 6 hours on average, which suggested that the slow rate of killing intrinsically limits the efficiency of antitumor T cell responses. The ability to visualize when, where, and how tumor cells are killed in vivo offers new perspectives for understanding how immune effectors survey cancer cells and how local tumor microenvironments may subvert immune responses.
The Journal of Clinical Investigation