Lineage reprogramming of tumor-infiltrating cytotoxic T lymphocytes using protein stem cell transcription factors

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dc.contributor.advisorXiao, Zhengguoen_US
dc.contributor.authorBhaduriHauck, Anjuli Lucijaen_US
dc.contributor.departmentAnimal Sciencesen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.date.accessioned2015-09-18T05:48:25Z
dc.date.available2015-09-18T05:48:25Z
dc.date.issued2015en_US
dc.description.abstractAdoptive cell transfer therapy (ACT) is one of the most promising immunotherapies against cancer. However, this treatment regimen requires the expansion of a small population of effector cells, known as tumor infiltrating lymphocytes, into the billions in order to overcome the immunosuppressive tumor microenvironment. The cytotoxic T lymphocytes (CTLs) within this invading immune cell population are the most critical components to kill the growing cancer cells. Nonetheless, the rapid expansion of already exhausted tumor-infiltrating cytotoxic T lymphocytes (TICTLs) may further push them to a terminally differentiated state that reduces their proliferative response upon antigen stimulation. Recently, induced pluripotent stem cells (iPSCs) generated from TICTLs have been suggested as a way to create a renewable source of rejuvenated tumor-specific CTLs, but retroviral reprogramming is inefficient, and can lead to an increased chance of tumorigenesis. To improve the expansion of TICTLs, we used transient protein exposure to SOX2, OCT4, and NANOG (SON) in order to push these exhausted TICTLs to a less differentiated stage, preferably stem cell-like memory CTLs (Tscm). These three transcription factors were transiently delivered using a nuclear protein delivery system. We found only the TICTLs treated with SON (STICTLs) exhibited an increased proliferation rate and extended survivability, independent of additional cytokines and antigen stimulation both in vitro and in vivo; effector CTLs did not respond to the SON regimen. These highly proliferative STICTLs could be associated with up regulation of certain genes related in cell cycle control, such as cyclin D1. Though these STICTLs still express a T cell receptor (TCR), as well as many critical downstream components, they were unable to elicit a reaction against antigen exposure. Though clearly not iPSCs, it is possible that the SON treatment had pushed the TICTLs into a state similar to an early double negative thymocyte. Our findings indicate that TICTLs are uniquely responsive to protein SON compared to naïve and effector CTLs; suggesting TICTLs may also be sensitive to regulation by other more lineage specific transcription factors, thus present new avenue for cancer immune therapy.en_US
dc.identifierhttps://doi.org/10.13016/M2HH0G
dc.identifier.urihttp://hdl.handle.net/1903/17013
dc.language.isoenen_US
dc.subject.pqcontrolledImmunologyen_US
dc.subject.pqcontrolledAnimal sciencesen_US
dc.subject.pqcontrolledAnimal diseasesen_US
dc.subject.pquncontrolledAdoptive Cell Transfer Therapyen_US
dc.subject.pquncontrolledCanceren_US
dc.subject.pquncontrolledCytotoxic T lymphocytesen_US
dc.subject.pquncontrolledLineage reprogrammingen_US
dc.titleLineage reprogramming of tumor-infiltrating cytotoxic T lymphocytes using protein stem cell transcription factorsen_US
dc.typeThesisen_US

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