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dc.contributor.authorAboelella, Nada
dc.date.accessioned2021-11-29T14:02:22Z
dc.date.available2021-11-29T14:02:22Z
dc.date.issued2022-05
dc.identifier.urihttp://hdl.handle.net/10675.2/624145
dc.description.abstractAdoptive T cell therapy (ACT) has shown promising therapeutic outcomes in patients with certain types of hematological malignancies. However, durable and curative antitumor effects have been observed in a small fraction of treated patients, and ACT has not been successful in treating patients with solid tumors. Hence, developing new strategies to overcome the challenges facing ACT and to enhance its potency are urgently needed for better therapeutic outcomes over a broader range of malignancies. A better understanding of how ACT works, and which pathways can be targeted will lead to the development of novel strategies to enhance the antitumor efficacy of ACT. A recent study published by Dr. Zhou’s research group revealed that inducing oxidative stress in tumor cells is critically involved in tumor rejection by ACT. In the current study, we employed the pro-oxidative feature of indomethacin (Indo), a prototypical non-steroidal anti-inflammatory drug (NSAID), to explore whether further intensifying ROS in tumor cells can synergize with cancer immunotherapy. We found that Indo as a pro-oxidant can augment the efficacy of ACT in multiple tumor models. Conversely, supplementation of the antioxidant L-Nacetyl cysteine (LNAC) abrogated the beneficial effect of Indo in ACT. Mechanistically, our data indicate that Indo treatment leads to enhanced expression of death receptor 5 (DR5) in tumor cells, rendering them more susceptible to TNF-related apoptosis-inducing ligand (TRAIL)-induced cell death. We found that tumor-specific T cells upregulated TRAIL expression upon adoptive transfer into hosts that had been pre-conditioned with cyclophosphamide (CTX). Using genetic-based approaches, we performed both gain-of function and loss-of-function studies to evaluate the role of the TRAIL-DR5 axis in the immunopotentiating effect of Indo in ACT. We showed that DR5-deficient tumor cells were unresponsive to the beneficial effect of Indo, while overexpressing TRAIL in donor T cells led to further improvement in mouse survival. Collectively, our study demonstrates that the pro-oxidative feature of selected NSAIDs can be exploited to augment the efficacy of T cell therapy. Our findings provide a strong rationale for targeting tumor redox to achieve more effective tumor destruction through the combination of pro-oxidants and ACT.
dc.publisherAugusta University
dc.subjectImmunology
dc.subjectOncology
dc.subjectAdoptive T cell Therapy, B cell lymphoma, CAR T cells, TCR, Death Receptor (DR5), Pro-oxidants, Indomethacin, TNF-related apoptosis-inducing ligand (TRAIL)
dc.titleINDOMETHACIN-INDUCED OXIDATIVE STRESS SENSITIZES TUMOR CELLS TO T CELL CYTOTOXICITY THROUGH THE TRAIL-DR5 AXIS
dc.typedissertationen_US
dc.contributor.departmentBiomedical Sciences
dc.language.rfc3066en
dc.date.updated2021-11-29T14:02:25Z
dc.description.advisorZhou, Gang
dc.description.committeeMunn, David
dc.description.committeeFukai, Tohru
dc.description.committeeBryan, Locke
dc.description.committeeHe, Yukai
dc.description.committeePacholczyk, Rafal
dc.description.degreePh.D.
refterms.dateFOA2022-05-19T13:46:19Z


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