Engineering second-generation TCR-T cells by site-specific integration of TRAF-binding motifs into the CD247 locusopen access
- Authors
- Lah, Sangjoon; Kim, Segi; Kang, In; Kim, Hyojin; Hupperetz, Cedric; Jung, Hyuncheol; Choi, Hyeong Ryeol; Lee, Young-Ho; Jang, Hyeon-Ki; Bae, Sangsu; Kim, Chan Hyuk
- Issue Date
- Apr-2023
- Publisher
- BMJ PUBLISHING GROUP
- Keywords
- cell engineering; costimulatory and inhibitory T-cell receptors; immunotherapy; T-lymphocytes
- Citation
- JOURNAL FOR IMMUNOTHERAPY OF CANCER, v.11, no.4, pp.1 - 15
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL FOR IMMUNOTHERAPY OF CANCER
- Volume
- 11
- Number
- 4
- Start Page
- 1
- End Page
- 15
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/185481
- DOI
- 10.1136/jitc-2022-005519
- ISSN
- 2051-1426
- Abstract
- BackgroundThe incorporation of co-stimulatory signaling domains into second-generation chimeric antigen receptors (CARs) significantly enhances the proliferation and persistence of CAR-T cells in vivo, leading to successful clinical outcomes.MethodsTo achieve such functional enhancement in transgenic T-cell receptor-engineered T-cell (TCR-T) therapy, we designed a second-generation TCR-T cell in which CD3 zeta genes modified to contain the intracellular domain (ICD) of the 4-1BB receptor were selectively inserted into the CD247 locus.ResultsThis modification enabled the simultaneous recruitment of key adaptor molecules for signals 1 and 2 on TCR engagement. However, the addition of full-length 4-1BB ICD unexpectedly impaired the expression and signaling of TCRs, leading to suboptimal antitumor activity of the resulting TCR-T cells in vivo. We found that the basic-rich motif (BRM) in the 4-1BB ICD was responsible for the undesirable outcomes, and that fusion of minimal tumor necrosis factor receptor-associated factor (TRAF)-binding motifs at the C-terminus of CD3 zeta (zBB(Delta BRM)) was sufficient to recruit TRAF2, the key adaptor molecule in 4-1BB signaling, while retaining the expression and proximal signaling of the transgenic TCR. Consequently, TCR-T cells expressing zBB(Delta BRM) exhibited improved persistence and expansion in vitro and in vivo, resulting in superior antitumor activity in a mouse xenograft model.ConclusionsOur findings offer a promising strategy for improving the intracellular signaling of TCR-T cells and their application in treating solid tumors.
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