CD8+ T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector differentiation within the tumor

Abstract

Improvements in tumor immunotherapies depend on better understanding of the anti-tumor Tcell response. By studying human tumor-draining lymph nodes (TDLNs), we found that activated CD8+ Tcells 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+ Tcells. Murine tumor models revealed that tumor-specific CD8+ Tcells 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+ Tcell activation in response to cancer is different from that of canonical CD8+ Tcell activation to acute viruses, and it proposes two stages of tumor-specific CD8+ Tcell activation: initial activation in TDLNs and subsequent effector program acquisition within the tumor after additional co-stimulation.