Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 35, Pages 17460-17469Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1904253116
Keywords
natural killer cells; lung adenocarcinoma; immunotherapy; adaptive immune response; antitumor immunity
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Funding
- Swanson Biotechnology Center Core in the Koch Institute at the Massachusetts Institute for Technology
- National Cancer Institute Cancer Center Support Grant [P30-CA14051]
- Howard Hughes Medical Institute
- NIH [1 U54 CA12651501, R01-CA185020-01]
- Margaret A. Cunningham Immune Mechanisms in Cancer Research Fellowship Award
- Ludwig Center for Molecular Oncology Graduate Student fellowship
- NIH Pre-Doctoral Training Grant [T32GM007287]
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Natural killer (NK) cells inhibit tumor development in mouse models and their presence in tumors correlates with patient survival. However, tumor-associated NK cells become dysfunctional; thus, stimulation of NK cells in cancer is emerging as an attractive immunotherapeutic strategy. In a mouse model of lung adenocarcinoma, NK cells localized to tumor stroma with immature phenotypes and low functional capacity. To test their responsiveness within established disease, we engineered a system for inducible expression of activating ligands in tumors. After stimulation, NK cells localized inside tumors, with increased cytokine production capacity. Strikingly, T cells were also recruited to tumors in an NK cell-dependent manner, and exhibited higher functionality. In neoantigen-expressing tumors, NK cell stimulation enhanced the number and function of tumor-specific T cells and, in long-term settings, reduced tumor growth. Thus, even in established disease NK cells can be activated to contribute to antitumor immunity, supporting their potential as an important target in cancer immunotherapy.
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