Motility and tumor infiltration are key aspects of invariant natural killer T cell anti-tumor function

Chenxi Tian, Yu Wang, Miya Su, Yuanyuan Huang, Yuwei Zhang, Jiaxiang Dou, Changfeng Zhao, Yuting Cai, Jun Pan, Shiyu Bai, Qielan Wu, Sanwei Chen, Shuhang Li, Di Xie, Rong Lv, Yusheng Chen, Yucai Wang, Sicheng Fu (), Huimin Zhang () and Li Bai ()
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Chenxi Tian: University of Science and Technology of China
Yu Wang: University of Science and Technology of China
Miya Su: University of Science and Technology of China
Yuanyuan Huang: University of Science and Technology of China
Yuwei Zhang: University of Science and Technology of China
Jiaxiang Dou: Hefei Comprehensive National Science Center
Changfeng Zhao: University of Science and Technology of China
Yuting Cai: University of Science and Technology of China
Jun Pan: University of Science and Technology of China
Shiyu Bai: University of Science and Technology of China
Qielan Wu: University of Science and Technology of China
Sanwei Chen: The First Affiliated Hospital of Anhui Medical University
Shuhang Li: University of Science and Technology of China
Di Xie: University of Science and Technology of China
Rong Lv: Anhui Blood Center
Yusheng Chen: Hefei Comprehensive National Science Center
Yucai Wang: University of Science and Technology of China
Sicheng Fu: University of Science and Technology of China
Huimin Zhang: University of Science and Technology of China
Li Bai: University of Science and Technology of China

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Dysfunction of invariant natural killer T (iNKT) cells contributes to immune resistance of tumors. Most mechanistic studies focus on their static functional status before or after activation, not considering motility as an important characteristic for antigen scanning and thus anti-tumor capability. Here we show via intravital imaging, that impaired motility of iNKT cells and their exclusion from tumors both contribute to the diminished anti-tumor iNKT cell response. Mechanistically, CD1d, expressed on macrophages, interferes with tumor infiltration of iNKT cells and iNKT-DC interactions but does not influence their intratumoral motility. VCAM1, expressed by cancer cells, restricts iNKT cell motility and inhibits their antigen scanning and activation by DCs via reducing CDC42 expression. Blocking VCAM1-CD49d signaling improves motility and activation of intratumoral iNKT cells, and consequently augments their anti-tumor function. Interference with macrophage-iNKT cell interactions further enhances the anti-tumor capability of iNKT cells. Thus, our findings provide a direction to enhance the efficacy of iNKT cell-based immunotherapy via motility regulation.

Date: 2024
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DOI: 10.1038/s41467-024-45208-z

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