Prokhnevska et al. showed that tumor-DLNs from patients undergoing surgery for prostate or kidney cancer had a population of activated PD1+TCF1hi CD127hiCD28hi CD8+ T cells, which lacked effector molecules and shared TCR clonality and functional, transcriptional, and epigenetic traits with stem-like CD8+ T cells in the matched tumor. In mouse tumor models, tumor-DLN CD8+ T cells with a parallel phenotype became stem-like on initial antigen activation and then migrated to tumors. In tumors, costimulation by cDC2s and mo-DCs was required, and IFN-I and IL-12 contributed to Tcf1+ stem-like cell differentiation/acquisition of effector functions.
Contributed by Paula Hochman
ABSTRACT: 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.