Cell | 积木化设计——细胞疗法中程序化基因调控的合成受体(加州大学与帕克癌症免疫疗法研究所)
发布于 2022-06-01 23:58
01
Iowis Zhu, Kole T Roybal, et al.
Cell, 2022.
In their previous study, they have developed synNotch receptors and combined them with CARs to engineer a two-step positive-feedback circuit. SynNotch receptors activate through a process of regulated intramembrane proteolysis (RIP), which includes a disintegrin and metalloprotease (ADAM)-mediated shedding of the extracellular domain (ECD), γ-secretase-mediated cleavage of the transmembrane domain (TMD), and release of an intracellular transcription factor (TF) that enters the nucleus to activate target genes transcription. Although the first generation synNotch receptors are powerful tools, some limitations hamper their further advancement to clinical translation.
In this study, to address these problems, the authors re-engineered them to generate novel synthetic intramembrane proteolysis receptors (SNIPRs), which are composed of a ligand-binding domain (LBD), ECD, TMD, a juxtamembrane domain (JMD), and TF. They selected human Robo1 as a prototypical SNIPR, a RIP receptor family member mediating ligand-directed neuronal pathfinding. They designed a modular strategy for receptor assembly to investigate the role of core domains involved in RIP. Their data indicated that ECD of synRobo was easily shed, but TMD and JMD of Robo1were hard processed. The results also demonstrated that different ECDs could influence the fidelity and sensitivity of the receptor. Subsequently, they tested the hinge regions derived from CD8a, CD28, or IgG of clinical CARs to optimize the ECD. Interestingly, the results revealed that SNIPR with CD8a hinge was the optimal design for further advancement due to its efficient, high-fidelity activation and compact size. Furthermore, their data demonstrated that TMD and JMD engineering could regulate receptor activity. Moreover, regulatable transcriptional output and enhanced sensitivity could be achieved through the modular assembly of SNIPRs. Finally, they showed that optimized SNIPRs were compatible with a series of human and programmable TFs. Importantly, T cells with humanized SNIPR-CAR circuits exhibited potent and precise anti-tumor activity in vivo.
DOI:10.1016/j.cell.2022.03.023
02
Overacre-Delgoffe AE, et al.
Immunity. 2021.
The microbiota is crucial for shaping the host immune response. Helicobacter hepaticus (Hhep) which resides mainly in the cecum and colon, induces local immune responses depending on the immune state of the host. In healthy state, Hhep colonization induces CD4+ T cells to differentiate into Treg or Tfh cells. However, Hhep drives the differentiation of inflammatory Hhep-specific Th1 and Th17 cells and colitis under immunodeficient conditions.
In this paper, the authors colonized mice with Hhep in AOM-DSS model of colitis associated CRC. The results revealed that Hhep colonization decreased colorectal cancer burden and caused an increase in CD4+T cells, B cells, and CD11c+ cells in the tumor. In addition, the ratio of CD4+Foxp3+ Treg cells to CD4+Foxp3- T cells decreased. To further understand the effects of Hhep colonization on the TME of CRC, they performed scRNA-seq on total cells from the tumor-containing epithelial layer (EL) and lamina propria (LP) layer. The data showed that Hhep-driven anti-tumor immunity was related to an increase in cytotoxic lymphocytes in and around tumors. To dissect the diversity of cell types in tumors, they did the antibody-mediated depletion experiments and the results revealed that Hhep-mediated anti-tumor immunity was independent of CD8+ T cells, but dependent on CD4+T cells. Therefore, they analyzed the colonic CD4+ T cell response to Hhep colonization and the results from flow cytometry of the colon LP showed an increased percentage of Tfh cells (CXCR5+PD1+CD4+ T cells). DRAGON clustering analysis of the LP indicated that lymphatic vessels expressed integrins and secreted cytokines that could recruit and support immune cells.
TLSs (tertiary lymphoid structures) are ectopic lymphoid organs that form in response to chronic inflammation. Their presence in or near tumors is associated with a positive prognosis for many tumors including CRC. The authors found that Hhep colonization drove an increase in lymphatics and TLSs in the colonic LP, that could better support T and B cell recruitment and the anti-tumor response. To track the location of Hhep-specific T cells within the colon, they transferred naive CD45.1+ Hhep-specific TCR tg CD4+ T cells into tumor-bearing Hhep-colonized mice 7 weeks post AOM administration. Hhep-specific CD4+ T cells were predominantly found within the TLSs inside or around the B cell follicle. To test the importance of Hhep-specific Tfh cells in TLS induction and control over CRC directly, they utilized AOM-DSS induction of CRC in Bcl6fl/flCd4Cre mice with Hhep. Their data indicated that Tfh cells were required for Hhep-driven formation of colonic TLSs, immune infiltration of the tumor, and control of tumor growth. Importantly, analysis of CRC patients in TCGA database showed that an enriched Tfh cell signature was observed in patients at a lower tumor stage and also related to longer progression-free survival.
doi: 10.1016/j.immuni.2021.11.003.
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