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NK and NKT cells have distinct properties and functions in cancer

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Abstract

Natural killer (NK) and natural killer T (NKT) cells are two important cell subsets of the innate immune system. NK and NKT cells share many phenotypes and functions for anti-tumor immunity; however, the dynamic changes in phenotypes and functional interactions within the tumor microenvironment during tumor development and progression are unknown. Here we report that NK and NKT cells have distinct properties, metabolic profiles, and functions during tumor development. Using the mouse E0771 breast cancer and B16 melanoma models, we found that both NK and NKT cells are dynamically involved in the immune responses to cancer but have distinct distributions and phenotypic profiles in tumor sites and other peripheral organs during the course of tumor development and progression. In the early stages of tumor development, both NK and NKT cells exhibit effector properties. In the later cancer stages, NK and NKT cells have impaired cytotoxic capacities and dysfunctional states. NK cells become senescent cells, while NKT cells, other than invariant NKT (iNKT) cells, are exhausted in the advanced cancers. In contrast, iNKT cells develop increases in activation and effector function within the breast tumor microenvironment. In addition, senescent NK cells have heightened glucose and lipid metabolism, but exhausted NKT cells display unbalanced metabolism in tumor microenvironments of both breast cancer and melanoma tumor models. These studies provide a better understanding of the dynamic and distinct functional roles of NK and NKT cells in anti-tumor immunity, which may facilitate the development of novel immunotherapies targeting NK and NKT cells for cancer treatment.

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Fig. 1: Distinct distributions of NK and NKT cells in the breast cancer E0771 tumor-bearing mice during the tumor development and progression.
Fig. 2: Characteristics of NK cells in the breast cancer E0771 tumor-bearing mice.
Fig. 3: Characteristics of NKT cells in the breast cancer E0771 tumor-bearing mice.
Fig. 4: NKT cells but not NK cells are exhausted in breast cancer E0771 tumor-bearing mice.
Fig. 5: iNKT cells have an activated state in the breast cancer tumor-bearing mice.
Fig. 6: NK cells are senescent cells induced by tumor cells in the tumor-bearing mice.
Fig. 7: NK and NKT cells in breast cancer have different metabolic profiles.

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Data availability

All data presented in this study are included in this published article and the supplementary information files.

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Acknowledgements

The authors would like to thank Dr. Qingsheng Mi at the Henry Ford Health System to provide mouse CD1d-PBS-57 and control CD1d-unloaded tetramers for the studies. We also thank Joy Eslick and Sherri Koehm for FACS and analyses.

Funding

This work was partially supported by grants from the American Cancer Society (RSG-10-160-01-LIB, to GP), Melanoma Research Alliance (to GP), and the NIH (CA184379, CA242188, CA237149, and AG067441 to GP).

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  1. These authors contributed equally: Xia Liu, Lingyun Li.

Authors and Affiliations

  1. Division of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, USA

    Xia Liu, Lingyun Li, Fusheng Si, Lan Huang, Yangjing Zhao, Chenchen Zhang, Daniel F. Hoft & Guangyong Peng

  2. Department of Molecular Microbiology & Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA

    Daniel F. Hoft & Guangyong Peng

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  1. Xia Liu
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Contributions

XL, LL, and GP: designed research, analyzed data, prepared figures and wrote the paper. XL, LL, FS, LH, YZ, and CZ performed experiments. DH: advised the design of research and discussed the manuscript.

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Correspondence to Guangyong Peng.

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All the animal experiments have been approved by the Institutional Animal Care Committee in Saint Louis University (protocol No. 2411).

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Liu, X., Li, L., Si, F. et al. NK and NKT cells have distinct properties and functions in cancer. Oncogene 40, 4521–4537 (2021). https://doi.org/10.1038/s41388-021-01880-9

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