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. 2022 Dec;24(12):1754-1765.
doi: 10.1038/s41556-022-01024-5. Epub 2022 Dec 6.

IL-2 delivery by engineered mesenchymal stem cells re-invigorates CD8+ T cells to overcome immunotherapy resistance in cancer

Joonbeom Bae #  1 , Longchao Liu #  1 , Casey Moore #  1   2 , Eric Hsu  1   2 , Anli Zhang  1 , Zhenhua Ren  1 , Zhichen Sun  1   3 , Xue Wang  1 , Jiankun Zhu  1 , Jiao Shen  4   5 , Jian Qiao  6 , Yang-Xin Fu  7   8
Affiliations

IL-2 delivery by engineered mesenchymal stem cells re-invigorates CD8+ T cells to overcome immunotherapy resistance in cancer

Joonbeom Bae et al. Nat Cell Biol. 2022 Dec.

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.

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