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Cancer Discov., Jun 18 2025, | https://doi.org/10.1158/2159-8290.CD-24-1232
Tumor-Associated NK Cells Regulate Distinct CD8+ T-cell Differentiation Program in Cancer and Contribute to Resistance against Immune Checkpoint Blockers
No-Joon Song1, Juan Xie1,2, Kyeong Joo Jung1,3, Yi Wang1, Joanna Pozniak4,5, Niccolo Roda4,5, Jean-Christophe Marine4,5, Brian P. Riesenberg1, Hyeongseon Jeon1,6, Anjun Ma1,6, Nathanael Cox1,7,8, Darren Wethington1,7,8, Kelsi Reynolds1, Tong Xiao1, Anqi Li1, Parker Kronen9, Nicholas Denko10, David P. Carbone1,11, Qin Ma1,6, William E. Carson III12, Bethany L. Mundy-Bosse1,9, Christin E. Burd1,13,14, Jayajit Das1,7,8, Dongjun Chung1,6, and Zihai Li1,11
1Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center- James Cancer Center and Solove Research Institute, Columbus, Ohio.
2The Interdisciplinary PhD Program in Biostatistics, The Ohio State University, Columbus, Ohio.
3Department of Computer Science and Engineering, The Ohio State University College of Engineering, Columbus, Ohio.
4Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium.
5Department of Oncology, Laboratory for Molecular Cancer Biology, KULeuven, Leuven, Belgium.
6Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, Ohio.
7Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.
8Steve and Cindy Rasmussen Institute for Genomics, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, Ohio.
9Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
10Department of Radiation Oncology, The Ohio State University, Columbus, Ohio.
11Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
12Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio.
13Department of Molecular Genetics, The Ohio State University, Columbus, Ohio.
14Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio.
Corresponding Author: Zihai Li
1Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center- James Cancer Center and Solove Research Institute, Columbus, Ohio.
2The Interdisciplinary PhD Program in Biostatistics, The Ohio State University, Columbus, Ohio.
3Department of Computer Science and Engineering, The Ohio State University College of Engineering, Columbus, Ohio.
4Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium.
5Department of Oncology, Laboratory for Molecular Cancer Biology, KULeuven, Leuven, Belgium.
6Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, Ohio.
7Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.
8Steve and Cindy Rasmussen Institute for Genomics, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, Ohio.
9Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
10Department of Radiation Oncology, The Ohio State University, Columbus, Ohio.
11Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
12Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio.
13Department of Molecular Genetics, The Ohio State University, Columbus, Ohio.
14Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio.
Corresponding Author: Zihai Li
Abstract
Immune checkpoint blockers (ICB) targeting the PD-1/PD-L1 axis represent established therapies for many cancers. However, resistance occurs in most patients due to complex immune-suppressive mechanisms in the tumor microenvironment. NK cells can play effector roles in tumor control, but their impact on T-cell dysfunction and ICB efficacy remains controversial. Through genetic and antibody-mediated NK cell depletion, we found that a subset of tumor-associated NK cells plays a negative role in ICB sensitivity; they further impede CD8+ T-cell differentiation toward a CD69+ BCL2+ EOMES+ GZMB+ TIM3- GITR- phenotype. Mechanistically, the retinoic acid receptor α-dependent differentiation program in CD8+ T cells is hindered by tumor-infiltrating NK cells via competition for IFNα and IL-2. Finally, we observed that lower frequencies of NK cells correlate with better clinical responses to ICBs in patients with cancer. These findings suggest potential avenues for enhancing CD8+ T cell-centered immunotherapy by targeting regulatory NK cells.
Although NK cells are traditionally viewed as antitumor effectors, our study uncovers their unexpected suppressive role in CD8+ T cell-based immunotherapy. By competing for cytokines, they disrupt retinoic acid receptor α-driven CD8+ T-cell differentiation and limit ICB efficacy. Clinically, reduced NK cell presence is associated with an enhanced immunotherapy response. See related article by Pozniak et al. p. XX.
논문정보
- Research article
- 2025년 06월 (BRIC 등록일 2025-07-04)
- 국외 연구진
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