Mechanical Immunoengineering of T cells for Therapeutic Applications

Lei, Kewen; Kurum, Armand; Tang, Li

doi:10.1021/acs.accounts.0c00486

Cited by 28 publications

(16 citation statements)

References 98 publications

(240 reference statements)

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“…With a longer reaction time (>12 h), PANITG was able to eventually generate similar amount of H 2 O 2 to that of the free GOx, suggesting that the activity of GOx would fully recover after the linker was cleaved. [ 18,20b,c,24 ] Overall, the TK linker was expected to be able to prevent the uncontrollable reaction between GOx and glucose during blood circulation to avoid inflammation of normal tissue, [ 20d,25 ] but the therapeutic effects would not be sacrificed as intact GOx was gradually released upon the linker cleavage. Therefore, the TK linker assures both the biocompatibility and the effectiveness of PANITG for potential cancer treatments.…”

Section: Resultsmentioning

confidence: 99%

Enzyme‐Engineered Conjugated Polymer Nanoplatform for Activatable Companion Diagnostics and Multistage Augmented Synergistic Therapy

Zhang

Jiang

et al. 2022

Advanced Materials

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Companion diagnostics (CDx) provides critical information for precision medicine. However, current CDx is mostly limited to in vitro tests, which cannot accurately evaluate the disease progression and treatment response in real time. To overcome this challenge, herein a glucose oxidase (GOx)‐engineered conjugated polymer (polyaniline, PANI) nanoplatform (denoted as PANITG) is reported for activatable imaging‐based CDx and multistage augmented photothermal/starvation synergistic therapy. PANITG comprises a pH‐activatable conjugated polymer as a photothermal convertor and photoacoustic (PA) emitter, a GOx as a cancer starvation inducer as well as a H2O2 and acid producer, and a H2O2‐cleavable linker as a “switch” for GOx activity. The in vivo PA imaging and photothermal therapy abilities are activated by acidic tumor microenvironment and self‐augmented by the reaction between GOx and glucose. Meanwhile, the photothermal effect will enhance the GOx activity in turn. Such multistage augmentation of the therapeutic effects will facilitate effective cancer management. In addition, the in vivo PA imaging with PANITG reveals the tumor pH level which is correlated to the efficiency of the photothermal therapy and to the catalytic activity of GOx at each stage, enabling real‐time activatable CDx.

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Section: Resultsmentioning

confidence: 99%

Enzyme‐Engineered Conjugated Polymer Nanoplatform for Activatable Companion Diagnostics and Multistage Augmented Synergistic Therapy

Zhang

Jiang

et al. 2022

Advanced Materials

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“…Our studies provide insight into the multidimensional mechanisms of immune suppression in tumours. The growing knowledge in fundamental mechano-immunology provides the basis for developing new engineering approaches to modulate biomechanical cues for enhanced antitumour immunity 53 – 56 . Leveraging cancer-cell mechanics and T-cell forces, as demonstrated in this study, may provide new therapeutic strategies in addition to conventional biochemical modulation.…”

Section: Discussionmentioning

confidence: 99%

Cancer-cell stiffening via cholesterol depletion enhances adoptive T-cell immunotherapy

et al. 2021

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Malignancy and tumour progression are associated with cancer-cell softening. Yet how the biomechanics of cancer cells affects T-cell mediated cytotoxicity and thus the outcomes of adoptive T-cell immunotherapies is unknown. Here, we show that T-cell-mediated cancer-cell killing is hampered for cortically soft cancer cells, whose plasma membrane is enriched with cholesterol, and that cancer-cell stiffening via cholesterol depletion augments T-cell cytotoxicity and enhances the efficacy of adoptive T-cell therapy against solid tumours in mice. We also show that the enhanced cytotoxicity against stiffened cancer cells is mediated by augmented T-cell forces arising from an increased accumulation of filamentous actin at the immunological synapse, and that cancer-cell stiffening has a negligible influence on T-cell-receptor signalling, on the production of cytolytic proteins such as granzyme B, on the secretion of interferon gamma and tumour necrosis factor alpha, and on Fas-receptor–Fas-ligand interactions. Our findings reveal a mechanical immune checkpoint that could be targeted therapeutically to improve the effectiveness of cancer immunotherapies. Cancer cells enriched with cholesterol in their plasma membrane impair T-cell mediated cytotoxicity, which can be augmented by stiffening the cancer cells via cholesterol depletion, as shown in mouse models of adoptive T-cell therapy.

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“…They could directly kill tumor cells and play a leading role in the process of tumor immunity. However, they would also differentiate into immunosuppressive cells to promote tumor development ( 5 , 6 ). Therefore, the dynamic balance of T cell clustering is particularly important in the fight between the body and tumor.…”

Section: Discussionmentioning

confidence: 99%

Characteristics and significance of T lymphocyte subsets in peripheral blood of osteosarcoma mice

Liu¹,

Xu²,

Xu³

et al. 2022

Transl Cancer Res TCR

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Background Osteosarcoma (OS) is the most common malignant bone tumor, which often has lung metastasis. The survival rate after tumor metastasis is very low. Treatments including the antitumor immunocompetence of innate immune cells are found favorable for OS tumor. However, as a major means of early tumor detection, there are still few studies on T cells in peripheral blood of OS patients. Methods OS cells were implanted into the femoral bone marrow cavity of C3H/HeN mice to construct OS model. The proportion of T lymphocyte subsets in peripheral blood of mice was detected by flow cytometry on the 14 th and 21 st days after modeling. Results Compared with sham operation group, on the 14 th day after operation, the proportion of γδT cells and CD4 + regulatory T cells (Tregs) showed significantly higher level while other subsets didn’t have obvious difference. On the 21 st day after operation, the proportion of CD3 + T cells, γδ T cells, CD4 + Tregs and Tregs/Th17 ratio were obviously higher than that of sham operation group. Meanwhile, while CD4 + T cells and CD8 + T cells were lower, suggesting the happen of peripheral immunosuppression. Comparing the T lymphocytes subsets on the 14 th and 21 st day after modeling in the tumor group, it was found that CD3 + T cells and CD4 + Tregs on the 21 st day after modeling were significantly higher than those on the 14 th day while CD4 + T cells, CD8 + T cells decreased significantly, indicating the changes of T lymphocytes in peripheral blood of OS mice are related to tumor development. Conclusions The formation and development of femoral OS is accompanied by the disorder of peripheral blood T lymphocyte subsets and peripheral immunosuppression.

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Mechanical Immunoengineering of T cells for Therapeutic Applications

Abstract: This work reports a redox-responsive nanogel backpack on the T cell surface for T cell receptorsignaling-triggered cytokine release, which boosts adoptive T cell therapy against solid tumors.

Cited by 28 publications

References 98 publications

Enzyme‐Engineered Conjugated Polymer Nanoplatform for Activatable Companion Diagnostics and Multistage Augmented Synergistic Therapy

Enzyme‐Engineered Conjugated Polymer Nanoplatform for Activatable Companion Diagnostics and Multistage Augmented Synergistic Therapy

Cancer-cell stiffening via cholesterol depletion enhances adoptive T-cell immunotherapy

Characteristics and significance of T lymphocyte subsets in peripheral blood of osteosarcoma mice

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