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Enhancing the Antitumor Activity of Nk-92 Natural Killer Cells by Ectopic Expression of Sodium Hydrogen Exchanger 1 / Yaoyu Gong.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Gong, Yaoyu, author.
- Language:
- English
- Subjects (All):
- Cellular biology.
- Immunology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Local Subjects:
- Cellular biology.
- Immunology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Physical Description:
- 1 online resource (153 pages)
- Distribution:
- Ann Arbor : ProQuest Dissertations & Theses, 2022
- Contained In:
- Dissertations Abstracts International 84-01B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.
- Language Note:
- English
- Summary:
- Adoptive cell transfer immunotherapy has remarkable efficacy against some hematological malignancies. However, its efficacy in solid tumors is limited by the adverse tumor microenvironment (TME) conditions, most notably that acidity inhibits T and NK cell mTORC1 activity and impairs cytotoxicity. In several reported studies, systemic buffering of tumor acidity enhanced the efficacy of immune checkpoint inhibitors. Paradoxically, we found in a Myc-inducible hepatocellular carcinoma model that buffering increased tumor mTORC1 activity, negating inhibition of tumor growth by anti-PD1 treatment. To avoid such adverse effects of systemic buffering favoring tumor growth, we overexpressed activated RHEB in the human NK-92 cell line, thereby rescuing acid-blunted mTORC1 activity and enhancing cytotoxicity. To mitigate the effect of acidity, we sought to metabolically engineer NK-92 cells with ectopically expressed acid extruder proteins. Whereas ectopic expression of carbonic anhydrase IX (CA9) moderately increased mTORC1 activity, it did not enhance effector function. In contrast, overexpressing a constitutively active Na+/H+-exchanger 1 (NHE1; SLC9A1) in NK-92 did not elevate mTORC1 but enhanced degranulation, target engagement, in vitro cytotoxicity, and in vivo antitumor activity. Our findings provide proof-of-concept that metabolic engineering of NK cells can enhance ACT for better efficacy against solid tumors without increasing mTORC1 activity.
- Notes:
- Source: Dissertations Abstracts International, Volume: 84-01, Section: B.
- Advisors: Dang, Chi Va; Committee members: Albelda, Steven M.; Holzbaur, Erika L. F.; Linette, Gerald P.; Simon, M. Celeste.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2022.
- Local Notes:
- School code: 0175
- ISBN:
- 9798834093350
- Access Restriction:
- Restricted for use by site license.
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