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Loss of type I IFN responsiveness impairs natural killer cell antitumor activity in breast cancer

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Abstract

Competent type I IFN signaling is the lynchpin of most immune surveillance mechanisms and has recently proven critical to the efficacy of several anticancer agents. Expression of the type I IFN receptor, IFNAR, underpins type I IFN responsiveness in all cells and facilitates the activation and cytotoxic potential of lymphocytes, while loss of IFNAR on lymphocytes has previously been associated with tumor progression and poor patient survival. This study underscores the importance of intact type I IFN signaling to NK cells in the regulation of tumorigenesis and metastasis, whereby ablation of NK cell IFNAR1 impairs antitumor activity and tumor clearance. Using a preclinical model of triple negative breast cancer, we identified that intact IFNAR on NK cells is required for an effective response to type I IFN-inducing immunotherapeutics that may be mediated by pathways associated with NK cell degranulation. Taken together, these data provide a rationale for considering the IFNAR status on NK cells when devising therapeutic strategies aimed at inducing systemic type I IFN signaling in breast cancer.

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Data availability

The authors declare that the data supporting the findings of this study are available within the paper (and its supplementary information files).

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Acknowledgements

We thank the LARTF and Peter MacCallum Cancer Centre animal facility staff for assistance monitoring experimental animals. We thank Dr. Paul Beavis for the gifting of the B16F10 cell line. We thank Prof Christian Engwerda and Dr Fiona Amante at the QIMR Berghofer for the gifting of C57BL/6 Ifnarfl/fl and NKp46iCre mice. We acknowledge fellowship support from the Victorian Cancer Agency (BSP) and grant funding from the Cancer Council Victoria (BSP) for this work.

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  1. Damien J. Zanker and Katie L. Owen contributed equally to this work

Authors and Affiliations

  1. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia

    Damien J. Zanker, Katie L. Owen, Alex J. Spurling & Belinda S. Parker

  2. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia

    Damien J. Zanker, Katie L. Owen & Belinda S. Parker

  3. Murdoch Children’s Research Institute, Parkville, VIC, 3052, Australia

    Nikola Baschuk

  4. Department of Biochemistry and Genetics, La Trobe Institute from Molecular Science, La Trobe University, Melbourne, VIC, 3086, Australia

    Belinda S. Parker

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Contributions

BSP and NB conceived the study. BSP, KLO and DZ designed the experiments. DZ, NB, KLO and AS performed the experiments. KLO and DZ analyzed and interpreted the data. BSP supervised the overall research. KLO and BSP wrote the paper. KLO, DZ, NB and BSP reviewed and/or edited the paper.

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Correspondence to Belinda S. Parker.

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Zanker, D.J., Owen, K.L., Baschuk, N. et al. Loss of type I IFN responsiveness impairs natural killer cell antitumor activity in breast cancer. Cancer Immunol Immunother 70, 2125–2138 (2021). https://doi.org/10.1007/s00262-021-02857-z

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