IMMUNOLOGY2025™ Conference Recordings-Early CD8+ T cell fate commitment in cancer and infection

Video Transcription

Video Summary

The speaker describes how T cells become dysfunctional in tumors very early, challenging the idea that exhaustion only develops gradually. Using a mouse liver cancer model and tumor-specific T cells, the lab showed that T cells activated in tumors proliferate normally but lose cytokine and granzyme function within hours, even before division. ATAC-seq and RNA-seq revealed that tumor and infection T cells diverge within 6 hours, with tumor cells rapidly turning on an exhaustion-associated PD-1 enhancer and chromatin programs that are then reinforced over time. Some early tumor-induced changes could partially reverse if cells were removed from the tumor quickly, but longer exposure made dysfunction harder to recover from.<br /><br />The talk then shifted to a second finding: TCF1, a key T-cell transcription factor, drops very early after antigen stimulation, rebounds, and then drops again during proliferation. This pre-division TCF1 drop is shaped by TCR strength and IL-12/inflammatory signaling. Early priming conditions leave a lasting imprint on whether T cells become more effector-like or memory-like, even after later exposures. Experiments reducing TCF1 during priming altered downstream differentiation and enhanced effector features in vivo. Overall, the speaker proposes that early antigen and inflammation cues program T-cell fate by setting TCF1-dependent epigenetic states.

Keywords

T cells

tumor exhaustion

TCF1

PD-1 enhancer

chromatin remodeling

liver cancer model

epigenetic programming