CD8⁺ T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector...

Improvements in tumor immunotherapies depend on better understanding of the anti-tumor T cell response. By studying human tumor-draining lymph nodes (TDLNs), we found that activated CD8⁺ T cells in TDLNs shared functional, transcriptional, and epigenetic traits with TCF1⁺ stem-like cells in the tumor. The phenotype and TCR overlap suggested that these TDLN cells were precursors to tumor-resident stem-like CD8⁺ T cells. Murine tumor models revealed that tumor-specific CD8⁺ T cells were activated in TDLNs but lacked an effector phenotype. These stem-like cells migrated into the tumor, where additional co-stimulation from antigen-presenting cells drove effector differentiation. This model of CD8⁺ T cell activation in response to cancer is different from that of canonical CD8⁺ T cell activation to acute viruses, and it proposes two stages of tumor-specific CD8⁺ T cell activation: initial activation in TDLNs and subsequent effector program acquisition within the tumor after additional co-stimulation.