DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | 김찬혁 | - |
dc.contributor.author | Lah, Sangjoon | - |
dc.contributor.author | 나상준 | - |
dc.date.accessioned | 2024-07-25T19:30:20Z | - |
dc.date.available | 2024-07-25T19:30:20Z | - |
dc.date.issued | 2022 | - |
dc.identifier.uri | http://library.kaist.ac.kr/search/detail/view.do?bibCtrlNo=1044817&flag=dissertation | en_US |
dc.identifier.uri | http://hdl.handle.net/10203/320417 | - |
dc.description | 학위논문(박사) - 한국과학기술원 : 의과학대학원, 2022.8,[v, 92 p. :] | - |
dc.description.abstract | The major therapeutic modality for treating cancer is the adoptive transfer of chimeric antigen receptor (CAR)- or transgenic T cell receptor (TCR)-T cells. The main advantages of the synthetic receptors are that it enables not only the redirection of T cell antigen specificity, but also the rewiring of signaling components to achieve optimal T cell activation. Indeed, the major breakthrough in the clinical success of CAR-T therapy has been the incorporation of a costimulatory domain in the cytoplasmic domain of a second-generation CAR, which led to a dramatic increase in their proliferation and persistence. Unlike CAR-T therapy, however, research on TCR-T therapy has so far focused primarily on identifying antigen-specific TCR repertoires.In this study, I developed second-generation TCR-T cells that simultaneously deliver TCR and co-stimulatory signals upon TCR stimulation. To achieved this, I generated a modified-CD3ζ that is fused with the signaling domain of the 4-1BB. The modified-CD3ζ recruited tumor necrosis factor receptor-associated factor 2 (TRAF2), a key adaptor of 4-1BB signaling, but exhibited diminished TCR signaling, resulting in a suboptimal anti-tumor effect in vivo. Based on the results of mutational studies, I further identified that a basic-rich motif (BRM) located in the 4-1BB signaling domain is responsible for the undesirable outcomes, likely due to the reinforced association between the modified-CD3ζ and the plasma membrane. Thus, I generated a modified-CD3ζ with BRM-truncated 4-1BB, termed zBBΔBRM. This modification was sufficient to recruit TRAF2 while preserving TCR signaling. Consequently, zBBΔBRM-based TCR-T cells demonstrated enhanced persistence with a higher expression of anti-apoptotic molecules upon repeated encounters with target cells. Subsequently, I confirmed significantly enhanced anti-tumor activity of my second-generation TCR-T cells, as compared to that of their first-generation counterparts, in a xenograft mouse model. Collectively, my findings offer a strategy for engineering signaling components of TCR-T cells, and in addition, provide a potential therapeutic approach for treatment of cancer. | - |
dc.language | eng | - |
dc.publisher | 한국과학기술원 | - |
dc.subject | 항암면역치료▼a카이메릭 항원 수용체 T세포▼a형질전환 T세포수용체-T 치료제▼aT세포수용체 복합체▼aCD3제타▼a4-1BB▼a산성-풍부 모티프 | - |
dc.subject | Cancer immunotherapy▼aCAR-T cells▼aTransgenic TCR-T cells▼aTCR complex▼aCD3ζ▼a4-1BB▼aBasic-rich motif | - |
dc.title | Enhancing the anti-tumor activity of TCR-engineered T cells by modified-CD3zeta fused with TRAF-binding motifs | - |
dc.title.alternative | 트레프 결합 모티프와 융합된 CD3제타에 의한 T세포수용체 조작 T 세포의 항암 효과 강화 | - |
dc.type | Thesis(Ph.D) | - |
dc.identifier.CNRN | 325007 | - |
dc.description.department | 한국과학기술원 :의과학대학원, | - |
dc.contributor.alternativeauthor | Kim, Chan Hyuk | - |
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