To overcome immune escape via downregulation of MHC-I expression, Hyungseok et al. focused on natural killer (NK) cells and demonstrated that anti-PD-1 combined with anti-Tim-3 combination therapy is more effective than either therapy alone to activate exhausted NK cells, and is further enhanced by intratumoral recombinant IL-21 (rIL21) treatment. rIL21 treatment increased recruitment of NK cells via CXRC3, but may also directly activate NK cells. Triple combination therapy was effective in multiple murine models of MHC class I-deficient tumors and ex vivo in human tumor samples.

Increased expression of co-inhibitory molecules such as PD-1 and Tim-3 on NK cells has been demonstrated in advanced cancer patients who harbor MHC class I-deficient tumors. However, even in preclinical models, the antitumor effects of checkpoint blockade on NK cells have not been clearly elucidated. Here, we show that anti-PD-1/anti-Tim-3 treatment suppressed tumor progression in mice bearing MHC class I-deficient tumors, and the suppression was further enhanced by recombinant IL21(rIL21) treatments through an NK cell-dependent mechanism. We also show that the intratumoral delivery of rIL21 attracted NK cells to the tumor site in a CXCR3-dependent fashion. A combination of IL21 and checkpoint blockade facilitated the effector function of exhausted NK cells in cancer patients. Given the effects of the checkpoint blockade and rIL21 combination on NK cells infiltrating into MHC class I-deficient tumors, we suggest that the efficacy of checkpoint blockade can be enhanced through the administration of IL21 for advanced cancer patients with MHC class I-low/deficient tumors.

Author Info: (1) Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National

Author Info: (1) Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University. (2) Research Institute of Pharmaceutical Sciences, Seoul National University. (3) Laboratory of Immunology, College of Pharmacy/Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University. (4) Surgery, Yonsei University College of Medicine. (5) Yonsei University College of Medicine. (6) Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine. (7) Laboratory of Immunology, College of Pharmacy/Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University cykang@snu.ac.kr.

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