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.

TGF-β has been shown to regulate stem-like CD8 + T cell differentiation into tissue resident memory T cells in chronic infection. Here authors show that in tumour-bearing mice, a similar TGF-βdependent CD8 + T cell differentiation program is carried out in the draining lymph nodes, which impedes generation of anti-tumor migratory effector T cells upon future vaccination.

Details

Title
TGF-β-dependent lymphoid tissue residency of stem-like T cells limits response to tumor vaccine
Author
Li, Guo 1 ; Srinivasan, Saranya 2   VIAFID ORCID Logo  ; Wang, Liwen 3 ; Ma, Chaoyu 2 ; Guo, Kai 4 ; Xiao, Wenhao 5 ; Liao, Wei 6 ; Mishra, Shruti 7 ; Zhang, Xin 8 ; Qiu, Yuanzheng 8 ; Lu, Qianjin 9 ; Liu, Yong 8   VIAFID ORCID Logo  ; Zhang, Nu 2   VIAFID ORCID Logo 

 Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, Department of Microbiology, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880); Xiangya Hospital, Central South University, Department of Otolaryngology Head and Neck Surgery, Changsha, China (GRID:grid.452223.0) (ISNI:0000 0004 1757 7615); Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Xiangya Hospital, Central South University, Changsha, China (GRID:grid.452223.0); Central South University, Clinical Research Center for Laryngopharyngeal and Voice Disorders in Hunan Province, Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164) 
 Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, Department of Microbiology, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880) 
 Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, Department of Microbiology, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880); Central South University, Department of Hematology, The Third Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164) 
 Xiangya Hospital, Central South University, Department of Otolaryngology Head and Neck Surgery, Changsha, China (GRID:grid.452223.0) (ISNI:0000 0004 1757 7615); Sun Yat-Sen University Cancer Center, Department of Medical Imaging, Guangzhou, China (GRID:grid.488530.2) (ISNI:0000 0004 1803 6191) 
 Xiangya Hospital, Central South University, Department of Otolaryngology Head and Neck Surgery, Changsha, China (GRID:grid.452223.0) (ISNI:0000 0004 1757 7615) 
 Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, Department of Microbiology, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880); Central South University, Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164); Hunan Children’s Hospital, Department of Dermatology, Changsha, China (GRID:grid.440223.3) (ISNI:0000 0004 1772 5147) 
 Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, Department of Microbiology, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880); Dana-Farber Cancer Institute, Harvard Medical School, Department of Cancer Immunology and Virology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
 Xiangya Hospital, Central South University, Department of Otolaryngology Head and Neck Surgery, Changsha, China (GRID:grid.452223.0) (ISNI:0000 0004 1757 7615); Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Xiangya Hospital, Central South University, Changsha, China (GRID:grid.452223.0); Central South University, Clinical Research Center for Laryngopharyngeal and Voice Disorders in Hunan Province, Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164); Central South University, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164) 
 Central South University, Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164); Chinese Academy of Medical Sciences and Peking Union Medical College, Hospital for Skin Diseases (Institute of Dermatology), Nanjing, China (GRID:grid.506261.6) (ISNI:0000 0001 0706 7839) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2724434344
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.