Natural killer (NK) cells can kill cancer cells via antibody-dependent cell-mediated cytotoxicity (ADCC): a tumor-associated IgG antibody binds to the Fcγ receptor CD16 on NK cells via the antibody Fc region and activates the cytotoxic functions of the NK cell. Here, we used PET imaging to assess NK cell migration to human epidermal growth factor receptor 2 (HER2)-positive HCC1954 breast tumors, examining the influence of HER2-targeted trastuzumab antibody treatment on NK cell tumor accumulation. Methods: Human NK cells from healthy donors were expanded ex vivo and labeled with [⁸⁹Zr]Zr-oxine. In vitro experiments compared the phenotypic markers, viability, proliferation, migration, degranulation, and ADCC behaviors of both labeled (⁸⁹Zr-NK) and unlabeled NK cells. Female mice bearing orthotopic human breast HCC1954 tumors were administered ⁸⁹Zr-NK cells alongside trastuzumab treatment or a sham treatment and then scanned using PET/CT imaging over 7 d. Flow cytometry and γ-counting were used to analyze the presence of ⁸⁹Zr-NK cells in liver and spleen tissues. Results: ⁸⁹Zr cell radiolabeling yields measured 42.2% ± 8.0%. At an average specific activity of 16.7 ± 4.7 kBq/10⁶ cells, ⁸⁹Zr-NK cells retained phenotypic and functional characteristics including CD56 and CD16 expression, viability, migration, degranulation, and ADCC capabilities. In vivo PET/CT studies indicated predominant accumulation of ⁸⁹Zr-NK cells in the liver and spleen. Ex vivo analyses of liver and spleen tissues indicated that the administered human ⁸⁹Zr-NK cells retained their radioactivity in vivo and that ⁸⁹Zr did not transfer to cells of murine soft tissues, thus validating this ⁸⁹Zr PET method for NK cell tracking. Notably, ⁸⁹Zr-NK cells migrated to HER2-positive tumors, both with and without trastuzumab treatment. Trastuzumab treatment was associated with an increased ⁸⁹Zr-NK cell signal at days 1 and 3 after injection. Conclusion: In vitro, ⁸⁹Zr-NK cells maintained key cellular and cytotoxic functions. In vivo, ⁸⁹Zr-NK cells trafficked to HER2-postive tumors, with trastuzumab treatment correlating with enhanced ⁸⁹Zr-NK infiltration. This study demonstrates the feasibility of using PET to image ⁸⁹Zr-NK cell infiltration into solid tumors.

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