TGF-β-dependent lymphoid tissue residency of stem-like T cells limits response to tumor vaccine

TGF-β signaling is necessary for CD8⁺ T cell differentiation into tissue resident memory T cells (T_RM). Although higher frequency of CD8⁺ T_RM cells in the tumor microenvironment is associated with better prognosis, TGF-β-blockade typically improves rather than worsens outcomes. Here we show that in a mouse melanoma model, in the tumor-draining lymph nodes (TDLN) rather than in the tumors themselves, stem-like CD8⁺ T cells differentiate into T_RMs in a TGF-β and tumor antigen dependent manner. Following vaccination against a melanoma-specific epitope, most tumour-specific CD8⁺ T cells are maintained in a stem-like state, but a proportion of cells lost T_RM status and differentiate into CX3CR1⁺ effector CD8⁺ T cells in the TDLN, which are subsequently migrating into the tumours. Disruption of TGF-β signaling changes the dynamics of these developmental processes, with the net result of improving effector CD8⁺ T cell migration into the tumours. In summary, TDLN stem-like T cells transiently switch from a TGF-β-dependent T_RM differentiation program to an anti-tumor migratory effector development upon vaccination, which transition can be facilitated by targeted TGF-β blockade.