@article{0611fcf9b23940e1916593fd8500b8f7,
title = "IL-2 delivery by engineered mesenchymal stem cells re-invigorates CD8+ T cells to overcome immunotherapy resistance in cancer",
abstract = "Immune checkpoint blockade (ICB)-based immunotherapy depends on functional tumour-infiltrating lymphocytes (TILs), but essential cytokines are less understood. Here we uncover an essential role of endogenous IL-2 for ICB responsiveness and the correlation between insufficient IL-2 signalling and T-cell exhaustion as tumours progress. To determine if exogenous IL-2 in the tumour microenvironment can overcome ICB resistance, we engineered mesenchymal stem cells (MSCs) to successfully deliver IL-2 mutein dimer (SIL2-EMSC) to TILs. While MSCs have been used to suppress inflammation, SIL2-EMSCs elicit anti-tumour immunity and overcome ICB resistance without toxicity. Mechanistically, SIL2-EMSCs activate and expand pre-existing CD8+ TILs, sufficient for tumour control and induction of systemic anti-tumour effects. Furthermore, engineered MSCs create synergy of innate and adaptive immunity. The therapeutic benefits of SIL2-EMSCs were also observed in humanized mouse models. Overall, engineered MSCs rejuvenate CD8+ TILs and thus potentiate ICB and chemotherapy.",
author = "Joonbeom Bae and Longchao Liu and Casey Moore and Eric Hsu and Anli Zhang and Zhenhua Ren and Zhichen Sun and Xue Wang and Jiankun Zhu and Jiao Shen and Jian Qiao and Fu, {Yang Xin}",
note = "Funding Information: This work was supported by Cancer Prevention and Research Institute of Texas (CPRIT) grant RR150072 given to Y.-X.F. and the NIH/NCI grant R01-CA240952 given to J.Q. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank the Institutional Animal Care and Use Committee Animal Resources Center, and Animal Research Center. SSR#69 plasmid was kindly provided by T. C. He at Chicago University. HIF-1 reporter p2.1 plasmid was kindly provided by W. Luo at UT Southwestern Medical Center. Human cord blood was kindly provided by R. A. Word at Obstetrics and Gynecology Tissue Procurement Facility in UT Southwestern Medical Center, supported by NIH-P01-HD087150. We also thank C. Han, Z. Liu, C. Lu, Y. Liang, X. Cao, C. Dong and B. Moon for providing experiment materials and helpful discussions. Funding Information: This work was supported by Cancer Prevention and Research Institute of Texas (CPRIT) grant RR150072 given to Y.-X.F. and the NIH/NCI grant R01-CA240952 given to J.Q. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank the Institutional Animal Care and Use Committee Animal Resources Center, and Animal Research Center. SSR#69 plasmid was kindly provided by T. C. He at Chicago University. HIF-1 reporter p2.1 plasmid was kindly provided by W. Luo at UT Southwestern Medical Center. Human cord blood was kindly provided by R. A. Word at Obstetrics and Gynecology Tissue Procurement Facility in UT Southwestern Medical Center, supported by NIH-P01-HD087150. We also thank C. Han, Z. Liu, C. Lu, Y. Liang, X. Cao, C. Dong and B. Moon for providing experiment materials and helpful discussions. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2022",
month = dec,
doi = "10.1038/s41556-022-01024-5",
language = "English (US)",
volume = "24",
pages = "1754--1765",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "12",
}