Authors: 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
Published: 2022-10-13
DOI: 10.1038/s41467-022-33768-x
Source: Full article
AbstractTGF-β signaling is necessary for CD8+T cell differentiation into tissue resident memory T cells (TRM). Although higher frequency of CD8+TRMcells 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 TRMs 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 TRMstatus 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 TRMdifferentiation program to an anti-tumor migratory effector development upon vaccination, which transition can be facilitated by targeted TGF-β blockade.