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 () and Nu Zhang ()
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Guo Li: Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio
Saranya Srinivasan: Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio
Liwen Wang: Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio
Chaoyu Ma: Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio
Kai Guo: Xiangya Hospital, Central South University
Wenhao Xiao: Xiangya Hospital, Central South University
Wei Liao: Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio
Shruti Mishra: Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio
Xin Zhang: Xiangya Hospital, Central South University
Yuanzheng Qiu: Xiangya Hospital, Central South University
Qianjin Lu: Central South University
Yong Liu: Xiangya Hospital, Central South University
Nu Zhang: Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract TGF-β signaling is necessary for CD8+ T cell differentiation into tissue resident memory T cells (TRM). Although higher frequency of CD8+ TRM 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 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 TRM 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 TRM differentiation program to an anti-tumor migratory effector development upon vaccination, which transition can be facilitated by targeted TGF-β blockade.

Date: 2022
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DOI: 10.1038/s41467-022-33768-x

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