PMID- 35574362 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220716 IS - 2234-943X (Print) IS - 2234-943X (Electronic) IS - 2234-943X (Linking) VI - 12 DP - 2022 TI - Human Tumor Targeted Cytotoxic Mast Cells for Cancer Immunotherapy. PG - 871390 LID - 10.3389/fonc.2022.871390 [doi] LID - 871390 AB - The diversity of autologous cells being used and investigated for cancer therapy continues to increase. Mast cells (MCs) are tissue cells that contain a unique set of anti-cancer mediators and are found in and around tumors. We sought to exploit the anti-tumor mediators in MC granules to selectively target them to tumor cells using tumor specific immunoglobin E (IgE) and controllably trigger release of anti-tumor mediators upon tumor cell engagement. We used a human HER2/neu-specific IgE to arm human MCs through the high affinity IgE receptor (FcepsilonRI). The ability of MCs to bind to and induce apoptosis of HER2/neu-positive cancer cells in vitro and in vivo was assessed. The interactions between MCs and cancer cells were investigated in real time using confocal microscopy. The mechanism of action using cytotoxic MCs was examined using gene array profiling. Genetically manipulating autologous MC to assess the effects of MC-specific mediators have on apoptosis of tumor cells was developed using siRNA. We found that HER2/neu tumor-specific IgE-sensitized MCs bound, penetrated, and killed HER2/neu-positive tumor masses in vitro. Tunneling nanotubes formed between MCs and tumor cells are described that parallel tumor cell apoptosis. In solid tumor, human breast cancer (BC) xenograft mouse models, infusion of HER2/neu IgE-sensitized human MCs co-localized to BC cells, decreased tumor burden, and prolonged overall survival without indications of toxicity. Gene microarray of tumor cells suggests a dependence on TNF and TGFbeta signaling pathways leading to apoptosis. Knocking down MC-released tryptase did not affect apoptosis of cancer cells. These studies suggest MCs can be polarized from Type I hypersensitivity-mediating cells to cytotoxic cells that selectively target tumor cells and specifically triggered to release anti-tumor mediators. A strategy to investigate which MC mediators are responsible for the observed tumor killing is described so that rational decisions can be made in the future when selecting which mediators to target for deletion or those that could further polarize them to cytotoxic MC by adding other known anti-tumor agents. Using autologous human MC may provide further options for cancer therapeutics that offers a unique anti-cancer mechanism of action using tumor targeted IgE's. CI - Copyright (c) 2022 Fereydouni, Ahani, Desai, Motaghed, Dellinger, Metcalfe, Yin, Lee, Kafri, Bhatt, Dellinger and Kepley. FAU - Fereydouni, Mohammad AU - Fereydouni M AD - Department of Nanoscience, Joint School of Nanoscience and Nanoengineering, University of North Carolina at Greensboro, Greensboro, NC, United States. FAU - Ahani, Elnaz AU - Ahani E AD - Department of Nanoengineering, Joint School of Nanoscience and Nanoengineering, North Carolina Agricultural and Technical (AT) State University, Greensboro, NC, United States. FAU - Desai, Parth AU - Desai P AD - Department of Nanoscience, Joint School of Nanoscience and Nanoengineering, University of North Carolina at Greensboro, Greensboro, NC, United States. FAU - Motaghed, Mona AU - Motaghed M AD - Department of Nanoengineering, Joint School of Nanoscience and Nanoengineering, North Carolina Agricultural and Technical (AT) State University, Greensboro, NC, United States. FAU - Dellinger, Anthony AU - Dellinger A AD - Department of Nanoscience, Joint School of Nanoscience and Nanoengineering, University of North Carolina at Greensboro, Greensboro, NC, United States. FAU - Metcalfe, Dean D AU - Metcalfe DD AD - Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States. FAU - Yin, Yuzhi AU - Yin Y AD - Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States. FAU - Lee, Sung Hyun AU - Lee SH AD - Gene Therapy Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. FAU - Kafri, Tal AU - Kafri T AD - Gene Therapy Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. FAU - Bhatt, Aadra P AU - Bhatt AP AD - Lineberger Comprehensive Cancer Center, and the Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. FAU - Dellinger, Kristen AU - Dellinger K AD - Department of Nanoengineering, Joint School of Nanoscience and Nanoengineering, North Carolina Agricultural and Technical (AT) State University, Greensboro, NC, United States. FAU - Kepley, Christopher L AU - Kepley CL AD - Department of Molecular and Cellular Sciences, Liberty University College of Osteopathic Medicine, Lynchburg, VA, United States. LA - eng PT - Journal Article DEP - 20220422 PL - Switzerland TA - Front Oncol JT - Frontiers in oncology JID - 101568867 PMC - PMC9097604 OTO - NOTNLM OT - AllergoOncology OT - FcepsilonRI OT - IgE OT - TNF-alpha OT - adoptive cellular transfer OT - breast cancer OT - cell-based cancer immunotherapy OT - mast cell COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/05/17 06:00 MHDA- 2022/05/17 06:01 PMCR- 2022/01/01 CRDT- 2022/05/16 04:42 PHST- 2022/02/08 00:00 [received] PHST- 2022/03/23 00:00 [accepted] PHST- 2022/05/16 04:42 [entrez] PHST- 2022/05/17 06:00 [pubmed] PHST- 2022/05/17 06:01 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fonc.2022.871390 [doi] PST - epublish SO - Front Oncol. 2022 Apr 22;12:871390. doi: 10.3389/fonc.2022.871390. eCollection 2022.