Restoration of Natural Killer Cell Antimetastatic Activity by IL12 and Checkpoint Blockade

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 24; pp. 7059 - 7071
• Main Authors: Ohs, Isabel, Ducimetière, Laura, Marinho, Joana, Kulig, Paulina, Becher, Burkhard, Tugues, Sonia
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 15.12.2017
• Subjects: Animals; Cancer; CD223 antigen; Cell Cycle Checkpoints - drug effects; Cell Cycle Checkpoints - genetics; Cell Cycle Checkpoints - immunology; Cytotoxicity; Cytotoxicity, Immunologic - genetics; Female; Gene Expression Regulation, Neoplastic - drug effects; Immune checkpoint; Immunostimulation; Immunotherapy; Immunotherapy - methods; Interleukin 1; Interleukin 12; Interleukin-12 - genetics; Interleukin-12 - pharmacology; Interleukin-12 - therapeutic use; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Lungs; Lymphocytes; Lymphocytes T; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - immunology; Mammary Neoplasms, Experimental - pathology; Mammary Neoplasms, Experimental - therapy; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Molecular Targeted Therapy - methods; Natural killer cells; Neoplasm Metastasis - genetics; Neoplasm Metastasis - immunology; PD-1 protein; T cell receptors; Tumor Cells, Cultured
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-17-1032

Immune checkpoint therapies target tumor antigen-specific T cells, but less is known about their effects on natural killer (NK) cells, which help control metastasis. In studying the development of lung metastases, we found that NK cells lose their cytotoxic capacity and acquire a molecular signature defined by the expression of coinhibitory receptors. In an effort to overcome this suppressive mechanism, we evaluated NK cell responses to the immunostimulatory cytokine IL12. Exposure to IL12 rescued the cytotoxicity of NK cells but also led to the emergence of an immature NK cell population that expressed high levels of the coinhibitory molecules PD-1, Lag-3, and TIGIT, thereby limiting NK cell-mediated control of pulmonary metastases. Notably, checkpoint blockade therapy synergized with IL12 to fully enable tumor control by NK cells, demonstrating that checkpoint blockers are not only applicable to enhance T cell-mediated immunotherapy, but also to restore the tumor-suppressive capacity of NK cells. .