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Targeting the activity of T cells by membrane surface redox regulation for cancer theranostics

Nature Nanotechnology volume 18, pages 86–97 (2023)Cite this article

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Abstract

T cells play a determining role in the immunomodulation and prognostic evaluation of cancer treatments relying on immune activation. While specific biomarkers determine the population and distribution of T cells in tumours, the in situ activity of T cells is less studied. Here we designed T-cell-targeting fusogenic liposomes to regulate and quantify the activity of T cells by exploiting their surface redox status as a chemical target. The T-cell-targeting fusogenic liposomes equipped with 2,2,6,6-tetramethylpiperidine (TEMP) groups neutralize reactive oxygen species protecting T cells from oxidation-induced loss of activity. Meanwhile, the production of paramagnetic 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) radicals allows magnetic resonance imaging quantification of the T cell activity. In multiple mouse models, the T-cell-targeting fusogenic liposomes led to efficient tumour inhibition and to early prediction of radiotherapy outcomes. This study uses a chemical targeting strategy to measure the in situ activity of T cells for cancer theranostics and may provide further understanding on engineering T cells for cancer treatment.

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Fig. 1: Targeting the activity of T cells by exploiting the –SH and S–S balance on the membrane surface of the T cells.
Fig. 2: Characterizations of fusogenic liposomes.
Fig. 3: MRI measurements of T-Fulips.
Fig. 4: T-Fulips enhance the activity of T cells by regulating –SH groups on the surface.
Fig. 5: T-Fulips regulate and quantify the activity of T cells in the RT of a mouse 4T1 tumour model.
Fig. 6: T-Fulips promote the therapeutic efficacy of adoptive T cell therapy in a B16F10-OVA model.

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Data availability

The main data that support the findings of this study are available within the Article, Supplementary Information and Supplementary Data 1. Other relevant data during the study are available for research purposes from the corresponding authors upon reasonable request. Source data are provided with this paper.

References

  1. Melero, I., Castanon, E., Alvarez, M., Champiat, S. & Marabelle, A. Intratumoural administration and tumour tissue targeting of cancer immunotherapies. Nat. Rev. Clin. Oncol. 18, 558–576 (2021).

    Article  CAS  Google Scholar 

  2. Lyu, L., Feng, Y., Chen, X. & Hu, Y. The global chimeric antigen receptor T (CAR-T) cell therapy patent landscape. Nat. Biotechnol. 38, 1387–1394 (2020).

    Article  CAS  Google Scholar 

  3. Nagarsheth, N. B. et al. TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. Nat. Med. 27, 419–425 (2021).

    Article  CAS  Google Scholar 

  4. Gong, N., Sheppard, N. C., Billingsley, M. M., June, C. H. & Mitchell, M. J. Nanomaterials for T-cell cancer immunotherapy. Nat. Nanotechnol. 16, 25–36 (2021).

    Article  CAS  Google Scholar 

  5. Morotti, M. et al. Promises and challenges of adoptive T-cell therapies for solid tumours. Brit. J. Cancer 124, 1759–1776 (2021).

    Article  Google Scholar 

  6. Galluzzi, L., Chan, T. A., Kroemer, G., Wolchok, J. D. & López-Soto, A. The hallmarks of successful anticancer immunotherapy. Sci. Transl. Med. 10, eaat7807 (2018).

    Article  Google Scholar 

  7. Levi, J. et al. Imaging of activated T cells as an early predictor of immune response to anti-PD-1 therapy. Cancer Res. 79, 3455–3465 (2019).

    Article  CAS  Google Scholar 

  8. Shi, C., Zhou, Z., Lin, H. & Gao, J. Imaging beyond seeing: early prognosis of cancer treatment. Small Methods 5, 2001025 (2021).

    Article  CAS  Google Scholar 

  9. Nishino, M., Hatabu, H. & Hodi, F. S. Imaging of cancer immunotherapy: current approaches and future directions. Radiology 290, 9–22 (2018).

    Article  Google Scholar 

  10. Scheper, W. et al. Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers. Nat. Med. 25, 89–94 (2019).

    Article  CAS  Google Scholar 

  11. Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).

    Article  CAS  Google Scholar 

  12. Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. New Engl. J. Med. 348, 203–213 (2003).

    Article  CAS  Google Scholar 

  13. Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

    Article  CAS  Google Scholar 

  14. Jin, M.-Z. & Jin, W.-L. The updated landscape of tumor microenvironment and drug repurposing. Signal Transduct. Target Ther. 5, 166 (2020).

    Article  Google Scholar 

  15. Gong, N. et al. Carbon-dot-supported atomically dispersed gold as a mitochondrial oxidative stress amplifier for cancer treatment. Nat. Nanotechnol. 14, 379–387 (2019).

    Article  CAS  Google Scholar 

  16. Tang, L. et al. Targeting neutrophils for enhanced cancer theranostics. Adv. Mater. 32, 2002739 (2020).

    Article  CAS  Google Scholar 

  17. Zanganeh, S. et al. Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nat. Nanotechnol. 11, 986–994 (2016).

    Article  CAS  Google Scholar 

  18. Gelderman, K. A., Hultqvist, M., Holmberg, J., Olofsson, P. & Holmdahl, R. T cell surface redox levels determine T cell reactivity and arthritis susceptibility. Proc. Natl Acad. Sci. USA 103, 12831–12836 (2006).

    Article  CAS  Google Scholar 

  19. Chakraborty, P. et al. Thioredoxin-1 improves the immunometabolic phenotype of antitumor T cells. J. Biol. Chem. 294, 9198–9212 (2019).

    Article  Google Scholar 

  20. Hogg, P. J. Disulfide bonds as switches for protein function. Trends Biochem. Sci. 28, 210–214 (2003).

    Article  CAS  Google Scholar 

  21. Sahaf, B., Heydari, K., Herzenberg, L. A. & Herzenberg, L. A. Lymphocyte surface thiol levels. Proc. Natl Acad. Sci. USA 100, 4001–4005 (2003).

    Article  CAS  Google Scholar 

  22. Deng, H. et al. Targeted scavenging of extracellular ROS relieves suppressive immunogenic cell death. Nat. Commun. 11, 4951 (2020).

    Article  CAS  Google Scholar 

  23. Gustafson, H. H., Holt-Casper, D., Grainger, D. W. & Ghandehari, H. Nanoparticle uptake: the phagocyte problem. Nano Today 10, 487–510 (2015).

    Article  CAS  Google Scholar 

  24. Sousa de Almeida, M. et al. Understanding nanoparticle endocytosis to improve targeting strategies in nanomedicine. Chem. Soc. Rev. 50, 5397–5434 (2021).

    Article  CAS  Google Scholar 

  25. Schmid, D. et al. T cell-targeting nanoparticles focus delivery of immunotherapy to improve antitumor immunity. Nat. Commun. 8, 1747 (2017).

    Article  Google Scholar 

  26. Arlauckas, S. P. et al. In vivo imaging reveals a tumor-associated macrophage–mediated resistance pathway in anti–PD-1 therapy. Sci. Transl. Med. 9, eaal3604 (2017).

    Article  Google Scholar 

  27. Ozsahin, M. et al. CD4 and CD8 T-lymphocyte apoptosis can predict radiation-induced late toxicity: a prospective study in 399 patients. Clin. Cancer Res. 11, 7426–7433 (2005).

    Article  CAS  Google Scholar 

  28. Wilkins, R. C., Kutzner, B. C., Truong, M. & McLean, J. R. N. The effect of the ratio of CD4+ to CD8+ T-cells on radiation-induced apoptosis in human lymphocyte subpopulations. Int. J. Radiat. Biol. 78, 681–688 (2002).

    Article  CAS  Google Scholar 

  29. Weichselbaum, R. R., Liang, H., Deng, L. & Fu, Y. X. Radiotherapy and immunotherapy: a beneficial liaison? Nat. Rev. Clin. Oncol. 14, 365–379 (2017).

    Article  CAS  Google Scholar 

  30. Zhou, Z. et al. Early stratification of radiotherapy response by activatable inflammation magnetic resonance imaging. Nat. Commun. 11, 3032 (2020).

    Article  CAS  Google Scholar 

  31. Restifo, N. P., Dudley, M. E. & Rosenberg, S. A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12, 269–281 (2012).

    Article  CAS  Google Scholar 

  32. Hammerl, D., Rieder, D., Martens, J. W. M., Trajanoski, Z. & Debets, R. Adoptive T cell therapy: new avenues leading to safe targets and powerful allies. Trends Immunol. 39, 921–936 (2018).

    Article  CAS  Google Scholar 

  33. Angelini, G. et al. Antigen-presenting dendritic cells provide the reducing extracellular microenvironment required for T lymphocyte activation. Proc. Natl Acad. Sci. USA 99, 1491–1496 (2002).

    Article  CAS  Google Scholar 

  34. Muri, J. & Kopf, M. Redox regulation of immunometabolism. Nat. Rev. Immunol. 21, 363–381 (2021).

    Article  CAS  Google Scholar 

  35. Hildeman, D. A., Mitchell, T., Kappler, J. & Marrack, P. T cell apoptosis and reactive oxygen species. J. Clin. Invest. 111, 575–581 (2003).

    Article  CAS  Google Scholar 

  36. Kouakanou, L. et al. Vitamin C promotes the proliferation and effector functions of human γδ T cells. Cell. Mol. Immunol. 17, 462–473 (2020).

    Article  CAS  Google Scholar 

  37. Pelly, V. S. et al. Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy. Cancer Discov. 11, 2602–2619 (2021).

  38. Tang, L. et al. Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery. Nat. Biotechnol. 36, 707–716 (2018).

    Article  CAS  Google Scholar 

  39. Alam, I. S. et al. Imaging activated T cells predicts response to cancer vaccines. J. Clin. Invest. 128, 2569–2580 (2018).

    Article  Google Scholar 

  40. Woodham, A. W. In vivo detection of antigen-specific CD8+ T cells by immuno-positron emission tomography. Nat. Methods 17, 1025–1032 (2020).

    Article  CAS  Google Scholar 

  41. Tavare, R. et al. An effective immuno-PET imaging method to monitor CD8-dependent responses to immunotherapy. Cancer Res. 76, 73–82 (2016).

    Article  CAS  Google Scholar 

  42. Guo, Y. et al. Metabolic reprogramming of terminally exhausted CD8+ T cells by IL-10 enhances anti-tumor immunity. Nat. Immunol. 22, 746–756 (2021).

    Article  CAS  Google Scholar 

  43. Scharping, N. E. et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat. Immunol. 22, 205–215 (2021).

    Article  CAS  Google Scholar 

  44. Kraaij, M. D. et al. Induction of regulatory T cells by macrophages is dependent on production of reactive oxygen species. Proc. Natl Acad. Sci. USA 107, 17686–17691 (2010).

    Article  CAS  Google Scholar 

  45. Yan, Z., Garg, S. K., Kipnis, J. & Banerjee, R. Extracellular redox modulation by regulatory T cells. Nat. Chem. Biol. 5, 721–723 (2009).

    Article  CAS  Google Scholar 

  46. Blakytny, R., Erkell, L. J. & Brunner, G. Inactivation of active and latent transforming growth factor beta by free thiols: potential redox regulation of biological action. Int. J. Biochem. Cell Biol. 38, 1363–1373 (2006).

    Article  CAS  Google Scholar 

  47. Laforge, M. et al. Tissue damage from neutrophil-induced oxidative stress in COVID-19. Nat. Rev. Immunol. 20, 515–516 (2020).

    Article  CAS  Google Scholar 

  48. Furman, D. et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25, 1822–1832 (2019).

    Article  CAS  Google Scholar 

  49. Wright, H. L., Moots, R. J. & Edwards, S. W. The multifactorial role of neutrophils in rheumatoid arthritis. Nat. Rev. Rheumatol. 10, 593–601 (2014).

    Article  CAS  Google Scholar 

  50. Csiszár, A. et al. Novel fusogenic liposomes for fluorescent cell labeling and membrane modification. Bioconjug. Chem. 21, 537–543 (2010).

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant no. 82272136, Z.Z.; no. 31971302, W.G.), the Special Project from the National Science and Technology Program for Central Guided Local Development (grant no. 2021L3010075, Z.Z.), the Start-up Programme from Xiamen University (Z.Z.), the project funded by China Postdoctoral Science Foundation (grant no. 2022M722654, C.S.), the National University of Singapore Start-up Grant (NUHSRO/2020/133/Startup/08, X.C.), National University of Singapore School of Medicine Nanomedicine Translational Research Program (NUHSRO/2021/034/TRP/09/Nanomedicine, X.C.) and National Medical Research Council Centre Grant Programme (CG21APR1005, X.C.). We cordially thank G. Liu and C. Liu for fruitful discussions, Z. Huang for her support in MRI scanning and D. Guo and X. Zhang from the School of Public Health at Xiamen University for their support in using the microscope and flow cytometer.

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  1. These authors contributed equally: Changrong Shi, Qianyu Zhang.

Authors and Affiliations

  1. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, China

    Changrong Shi, Qianyu Zhang, Fantian Zeng, Chao Du, Sureya Nijiati, Xuejun Wen, Xinyi Zhang, Hongzhang Yang, Zhide Guo, Xianzhong Zhang & Zijian Zhou

  2. Department of Minimally Invasive Interventional Radiology, State Key Laboratory of Respiratory Disease, School of Biomedical Engineering & the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

    Yuying Yao, Haoting Chen & Weisheng Guo

  3. State Key Laboratory of Physical Chemistry of Solid Surfaces & The Key Laboratory for Chemical Biology of Fujian Province, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China

    Jinhao Gao

  4. Departments of Diagnostic Radiology, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore

    Xiaoyuan Chen

  5. Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Xiaoyuan Chen

  6. Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Xiaoyuan Chen

  7. Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore

    Xiaoyuan Chen

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  1. Changrong Shi
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Contributions

Z.Z., C.S., W.G. and X.C. conceived and designed the project. C.S., F.Z., C.D., Q.Z. and H.Y. performed the material synthesis and characterizations. C.S. and Q.Z. prepared the samples. C.S. and Q.Z. acquired and analysed all the MRI data. C.S., Q.Z., Y.Y., Xinyi Zhang, S.N., F.Z., C.D. and H.C. performed the animal study. X.W., Z.G., Xianzhong Zhang and J.G. analysed and discussed the results. C.S., Z.Z., W.G. and X.C. analysed the results and cowrote the paper. All the authors discussed and approved the final version.

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Correspondence to Weisheng Guo, Xiaoyuan Chen or Zijian Zhou.

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Shi, C., Zhang, Q., Yao, Y. et al. Targeting the activity of T cells by membrane surface redox regulation for cancer theranostics. Nat. Nanotechnol. 18, 86–97 (2023). https://doi.org/10.1038/s41565-022-01261-7

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