TGF-β-dependent lymphoid tissue residency of stem-like T cells limits response to tumor vaccine
Guo Li, Saranya Srinivasan, Liwen Wang, Chaoyu Ma, Kai Guo, Wenhao Xiao, Wei Liao, Shruti Mishra, Xin Zhang, Yuanzheng Qiu, Qianjin Lu, Yong Liu, Nu Zhang
Abstract
Abstract 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 RM s 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.