journal contribution
posted on 2024-10-01, 07:41 authored by Yongjing Shi, Xiaodong Zheng, Hui Peng, Chenqi Xu, Rui Sun, Zhigang Tian, Haoyu Sun, Xianwei Wang Supplementary Figure S6. FBXO38 deficiency increases the expression of suppressors of cell cycle program in TINK cells
Funding
National Key Research and Development Program of China (NKPs)
National Natural Science Foundation of China (NSFC)
Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS)
Institute of Health and Medicine, Hefei Comprehensive National Science Center
History
ARTICLE ABSTRACT
Natural killer (NK) cells are the main innate antitumor effector cells but their function is often constrained in the tumor microenvironment. It has been reported that the E3 ligase FBXO38 accelerates PD-1 degradation in tumor-infiltrating T cells to unleash their cytotoxic function. In this study, we found that the transcriptional levels of FBXO38 in intratumoral NK cells of patients with cancer and tumor-bearing mice were significantly lower than in peritumoral NK cells. Conditional knockout of FBXO38 in NK cells accelerated tumor growth and increased tumor metastasis. FBXO38 deficiency resulted in impaired proliferation and survival of tumor-infiltrating NK (TINK) cells. Mechanistically, FBXO38 deficiency enhanced TGF-β signaling, including elevating expression of Smad2 and Smad3, which suppressed expression of the transcription factor Eomes and further reduced expression of surface IL15Rβ and IL15Rγc on NK cells. Consequently, FBXO38 deficiency led to TINK cell hyporesponsiveness to IL15. Consistent with these observations, FBXO38 mRNA expression was positively correlated with the proliferation of TINK cells in multiple human tumors. To study the therapeutic potential of FBXO38, mice bearing human tumors were treated with FBXO38 overexpressed human primary NK cells and showed a significant reduction in tumor size and prolonged survival. In conclusion, our results suggest that FBXO38 sustains NK-cell expansion and survival to promote antitumor immunity and have potential therapeutic implications as they suggest FBXO38 could be harnessed to enhance NK cell–based cancer immunotherapy.
