Toll-like receptor 2 costimulation potentiates the antitumor efficacy of CAR T Cells

Lai, Yunxin; Weng, Jianyu; Wei, Xinru; Qin, Le; Lai, Peilong; Zhao, Ruocong; Jiang, Zhiwu; Li, B; Lin, Shudong; Wang, S; Wu, Qianni; Tang, Zhaoyang; Liu, P; Pei, Duanqing; Yao, Yikun; Du, Xin; Li, P

doi:10.1038/leu.2017.249

Cited by 87 publications

(70 citation statements)

References 43 publications

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“…52 The incorporation of a TLR2 endodomain into CD28-costimulated second-generation CARs enhanced CAR T cell activity against CD19 and mesothelin-expressing tumors. 53,54 A further innovation in accessory domains is the inclusion of cytoplasmic domains of common cytokine receptors into the CAR endodomain ( Figure 3). Kagoya et al engineered a truncated IL-2Rb cytoplasmic domain, together with a STAT3-binding (YXXQ) motif into 4-1BBf and CD28f CARs.…”

Section: Other Costimulatory Domainsmentioning

confidence: 99%

Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations

et al. 2019

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Costimulatory signals are required to achieve robust chimeric antigen receptor (CAR) T cell expansion, function, persistence and antitumor activity. These can be provided by incorporating intracellular signalling domains from one or more T cell costimulatory molecules, such as CD28 or 4‐1BB, into the CAR. The selection and positioning of costimulatory domains within a CAR construct influence CAR T cell function and fate, and clinical experience of autologous anti‐CD19 CAR T cell therapies suggests that costimulatory domains have differential impacts on CAR T cell kinetics, cytotoxic function and potentially safety profile. The clinical impacts of combining costimulatory domains and of alternative costimulatory domains are not yet clearly established, and may be construct‐ and disease‐specific. The aim of this review is to summarise the function and effect of established and emerging costimulatory domains and their combinations within CAR T cells.

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Section: Other Costimulatory Domainsmentioning

confidence: 99%

Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations

et al. 2019

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“…20 To confirm the expression of NKG2D and DAP10 in CAR-T cells, we detected NKG2D expression on in vitro-expanded CAR-T cells by FACS, and most of the expression was detected on CD8+ CAR-T cells (Supplementary Figure 1A). DAP10 gene expression in these cells was then confirmed by qRT-PCR (Supplementary Figure 1B).…”

Section: Resultsmentioning

confidence: 97%

“…16–19 Previously, we determined that co-stimulation of toll-like receptor 2 can potentiate the anti-tumor efficacy of CAR-T cell. 20 Together, these findings demonstrate the importance of optimizing the co-stimulatory molecules in CAR-T cells.…”

Section: Introductionmentioning

confidence: 83%

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DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells

et al. 2018

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Chimeric antigen receptor (CAR) T cell immunotherapies have shown remarkable efficacy in treating multiple types of hematological malignancies but are not sufficiently effective at treating solid tumors. NKG2D is a strong activating receptor for NK cells and a co-stimulatory receptor for T cells. NKG2D signal transduction depends on DNAX-activating protein 10 (DAP10). Here, we introduced the cytoplasmic domain of DAP10 into the second-generation CARs M28z and G28z to generate M28z10 and G28z10, which target mesothelin (MSLN) and glypican 3 (GPC3), respectively. T cells expressing M28z10 or G28z10 showed enhanced and prolonged effector function against MSLN+ lung cancer or GPC3+ hepatocellular carcinoma cell lines in culture and secreted elevated levels of cytokines, including IL-2, IFN-γ, granzyme B, and GM-CSF. In addition, M28z10 CAR-T cells showed greater anti-tumor activity than those expressing M28z in both A549 cell line xenografts and human lung cancer patient-derived xenografts (PDX). Similarly, G28z10 exhibited higher efficacy in causing tumor regression than did G28z in hepatocellular carcinoma PDX. Therefore, our results show that DAP10 signaling contributes to the function of CAR-T cells in both lung cancer and hepatocellular carcinoma and can enhance the efficacy of CAR-T cells.

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“…1 T cell therapy, especially with chimeric antigen receptor T (CAR-T) cells, is promising for the treatment of leukemia and other cancers. 2,3 However, in the context of persistent antigen exposure in chronic viral infections and cancer, both native and adoptive T cells can become exhausted/dysfunctional. 4,5 These exhausted T cells upregulate multiple inhibitory receptors/immune checkpoints, such as CTLA-4 and PD-1, and exhibit defective proliferative capacities and cytokine production.…”

Section: Introductionmentioning

confidence: 99%

Leukemia cell-derived microvesicles induce T cell exhaustion via miRNA delivery

Cui

Luo

et al. 2018

OncoImmunology

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T cell function in cancer patients is usually impaired due to the constitutive activation of immune checkpoint inhibitors. This state is known as 'exhaustion' and is often associated with the inefficient control of tumors or persistent infections. In this work, we investigated the role of leukemia cell-derived microvesicles (MVs) in T cell exhaustion. Following incubation with MVs from various sources, all T cell subtypes exhibited the exhaustion phonotype and impaired cytokine secretion in vitro. Mice models also showed the connection between immune checkpoint inhibitors and MV injection. Sequencing and bioinformatics analyses indicated that a number of transcription factors and microRNAs (miRNAs) were attributable to the dysregulation of pathways and exhaustion in T cells. Further work revealed that functional miR-92a-3p, miR-21-5p, miR-16-5p, miR-126 and miR-182-5p in MVs could be delivered into T cells to induce the exhaustion phenotype. SerpinB2, IL-1β and CXCL5, which are mediators of the NF-κB pathway, were identified as the targets of the miRNAs mentioned above. We demonstrated that leukemia-derived MVs could initiate T cell exhaustion via the progressive temporal delivery of multiple exogenous miRNAs into T cells and the subsequent interaction of these miRNAs with their targets. Therefore, MVs can be expected not only to become new indicators of the T cell status in patients but also to be used as novel targets for personalized patient treatment.

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Toll-like receptor 2 costimulation potentiates the antitumor efficacy of CAR T Cells

Cited by 87 publications

References 43 publications

Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations

Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations

DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells

Leukemia cell-derived microvesicles induce T cell exhaustion via miRNA delivery

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