The first detailed investigation of CD8+ tumor-infiltrating T cell differentiation in the hours after cells enter a tumor has yielded an unexpected twist. Naive T cells veer away from effector fate and enter the path towards exhaustion much earlier than expected.
Rudloff et al.3 used mice with advanced liver cancers induced by the expression of oncogenic SV40 large T antigen in hepatocytes from birth onward. They adoptively transferred naive transgenic CD8+ T cells that recognize large T antigen, and tracked effector function, chromatin accessibility and gene expression of tumor-infiltrating lymphocytes (TILs) between 6 and 60 h after transfer. The same TCR-transgenic T cells mounting an effector response against an infection with Listeria monocytogenes expressing T antigen were used for comparison. T cells under the two experimental conditions exhibited comparable proliferation throughout the observation period, and upregulated CD44 and CD69, which indicates effective transmission of an initial activating signal. However, unlike effector T cells in the infection model, TILs were not able to produce the effector cytokine interferon-γ (IFNγ) or to degranulate in response to ex vivo stimulation. The early failure to acquire effector function can be assessed readily in this model because transferred T cells have immediate access to the liver<a data-track="click" data-track-action="reference anchor" data-track-label="link"