Attenuating NKG2D stimulation reshapes intratumoral NK cell functional state to enhance persistence and anti-tumor efficacy

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Abstract

NK cell-based therapies for solid tumors are limited by poor persistence and progressive functional impairment. Here, we investigated how the strength of NKG2D stimulation shapes NK cell fate and therapeutic efficacy. Using B10G5, a MICA/B-targeting partial agonist antibody that attenuates NKG2D stimulation, we show that reduced NKG2D stimulation reshapes the intratumoral NK cell compartment by enriching EOMEShiTCF1hi stem-like NK (stemNK) cell pool, preserving functional diversity, and limiting mitochondrial oxidative stress and exhaustion induced by chronic sMIC/MIC exposure. Mechanistically, we identified the H3K27me3 demethylase KDM6B as a conserved regulator of NK cell stemness whose enzymatic activity is required to maintain the intratumoral stemNK cell pool. Conversely, strong NKG2D stimulation induced mitochondrial ROS accumulation and upregulated the inhibitory receptor LAG3 on NK cells. Attenuated NKG2D stimulation on human NK cells increased KDM6B expression and reduced repressive H3K27me3 mark at the TCF7 locus. Importantly, attenuated NKG2D stimulation during ex vivo expansion enhanced human NK cell in vivo persistence and antitumor efficacy following adoptive transfer. Together, these findings establish NKG2D stimulation strength as a key determinant of NK cell fate and function in solid tumors and identify a translatable concept to improve NK cell-based immunotherapy for solid tumors.

Authors

Sizhe Liu, Ryan J. Brown, Payal Dhar, Geetha Priyanka Yerradoddi, Tyler A. Smith, Bin Zhang, Deyu Fang, Congcong He, David J. VanderWeele, Masha Kocherginsky, Arabela Grigorescu, Seth M. Pollack, Qingshu Meng, Qi Cao, Karla Guerra, Weiguo Cui, Jennifer D. Wu