Sequential therapy with supercharged NK cells with either chemotherapy drug cisplatin or anti-PD-1 antibody decreases the tumor size and significantly enhances the NK function in Hu-BLT mice Kawaljit Kaur 1 , Po-Chun Chen 1 , Meng-Wei Ko 1 , Ao Mei 2 , Emanuela Senjor 1,3,4 , Subramaniam Malarkannan 2,5 , Janko Kos 3,4 and Anahid Jewett 1,6 * 1 Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, Los Angeles, CA, United States, 2 Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI, United States, 3 Department of Biotechnology, Jozˇ ef Stefan Institute, Ljubljana, Slovenia, 4 Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia, 5 Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, United States, 6 The Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA) School of Dentistry and Medicine, Los Angeles, CA, United States Introduction and methods: In this study we report that sequential treatment of supercharged NK (sNK) cells with either chemotherapeutic drugs or check-point inhibitors eliminate both poorly differentiated and well differentiated tumors in- vivo in humanized-BLT mice. Background and results: sNK cells were found to be a unique population of activated NK cells with genetic, proteomic, and functional attributes that are very different from primary untreated or IL-2 treated NK cells. Furthermore, NK- supernatant differentiated or well-differentiated oral or pancreatic tumor cell lines are not susceptible to IL-2 activated primary NK cell-mediated cytotoxicity; however, they are greatly killed by the CDDP and paclitaxel in in-vitro assays. Injection of one dose of sNK cells at 1 million cells per mouse to aggressive CSC- like/poorly differentiated oral tumor bearing mice, followed by an injection of CDDP, inhibited tumor weight and growth, and increased IFN-g secretion as well as NK cell-mediated cytotoxicity substantially in bone marrow, spleen and peripheral blood derived immune cells. Similarly, the use of check point inhibitor anti-PD-1 antibody increased IFN-g secretion and NK cell-mediated cytotoxicity, and decreased the tumor burden in-vivo, and tumor growth of resected minimal residual tumors from hu-BLT mice when used sequentially Frontiers in Immunology frontiersin.org 01 OPEN ACCESS EDITED BY Catherine Sautes-Fridman, INSERM U1138 Centre de Recherche des Cordeliers (CRC), France REVIEWED BY Monika Holubova´ , Charles University, Czechia Jennifer D. Wu, Northwestern University, United States *CORRESPONDENCE Anahid Jewett ajewett@mednet.ucla.edu RECEIVED 27 December 2022 ACCEPTED 31 March 2023 PUBLISHED 01 May 2023 CITATION Kaur K, Chen P-C, Ko M-W, Mei A, Senjor E, Malarkannan S, Kos J and Jewett A (2023) Sequential therapy with supercharged NK cells with either chemotherapy drug cisplatin or anti-PD-1 antibody decreases the tumor size and significantly enhances the NK function in Hu-BLT mice. Front. Immunol. 14:1132807. doi: 10.3389/fimmu.2023.1132807 COPYRIGHT © 2023 Kaur, Chen, Ko, Mei, Senjor, Malarkannan, Kos and Jewett. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Original Research PUBLISHED 01 May 2023 DOI 10.3389/fimmu.2023.1132807