Fatty acid oxidation fuels natural killer cell responses against infection and cancer

Author:

Sheppard Sam12ORCID,Srpan Katja3ORCID,Lin Wendy4,Lee Mariah1ORCID,Delconte Rebecca B.1ORCID,Owyong Mark15,Carmeliet Peter6ORCID,Davis Daniel M.2ORCID,Xavier Joao B.4ORCID,Hsu Katharine C.3,Sun Joseph C.15

Affiliation:

1. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065

2. Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London SW7 2AZ, United Kingdom

3. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065

4. Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065

5. Immunology and Microbial Pathogenesis Program, Graduate School of Medical Sciences, Weill Cornell Medical College, New York, NY 10065

6. Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie and Department of Oncology, Leuven Cancer Institute, Katholieke Universiteit Leuven, Leuven 3000, Belgium

Abstract

Natural killer (NK) cells are a vital part of the innate immune system capable of rapidly clearing mutated or infected cells from the body and promoting an immune response. Here, we find that NK cells activated by viral infection or tumor challenge increase uptake of fatty acids and their expression of carnitine palmitoyltransferase I (CPT1A), a critical enzyme for long-chain fatty acid oxidation. Using a mouse model with an NK cell–specific deletion of CPT1A, combined with stable 13 C isotope tracing, we observe reduced mitochondrial function and fatty acid–derived aspartate production in CPT1A-deficient NK cells. Furthermore, CPT1A-deficient NK cells show reduced proliferation after viral infection and diminished protection against cancer due to impaired actin cytoskeleton rearrangement. Together, our findings highlight that fatty acid oxidation promotes NK cell metabolic resilience, processes that can be optimized in NK cell–based immunotherapies.

Funder

HHS | NIH | National Institute of Allergy and Infectious Diseases

HHS | NIH | National Cancer Institute

Publisher

Proceedings of the National Academy of Sciences

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