1. Academic Validation
  2. The E3 ubiquitin ligase FBXO38 maintains the antitumor function of natural killer cells by sustaining IL-15R signaling

The E3 ubiquitin ligase FBXO38 maintains the antitumor function of natural killer cells by sustaining IL-15R signaling

  • Cancer Immunol Res. 2024 Jul 11. doi: 10.1158/2326-6066.CIR-23-1061.
Yongjing Shi 1 Xiaodong Zheng 1 Hui Peng 2 Chenqi Xu 3 Rui Sun 1 Zhigang Tian 1 Haoyu Sun 4 Xianwei Wang 2
Affiliations

Affiliations

  • 1 University of Science and Technology of China, Hefei, Anhui, China.
  • 2 University of Science and Technology of China, Hefei, China.
  • 3 Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Medical Sciences, Shanghai, China.
  • 4 Fudan University, Shanghai, China.
Abstract

Natural killer (NK) cells are the main innate antitumor effector cells but their function is often constrained in the tumor microenvironment (TME). 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 Cancer patients and tumor-bearing mice were significantly lower than in peritumoral NK cells. Conditional knock-out (cKO) 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 IL-15Rβ and IL-15Rγc on NK cells. Consequently, FBXO38 deficiency led to TINK cell hyporesponsiveness to IL-15. 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.

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