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

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.

Automated summary

This study highlights the essential role of endogenous IL-2 in immune checkpoint blockade-based immunotherapy and reveals the correlation between insufficient IL-2 signaling and T-cell exhaustion during tumor progression. The study also demonstrates that engineered mesenchymal stem cells (MSCs) delivering IL-2 can overcome ICB resistance and elicit anti-tumor immunity without toxicity. Engineered MSCs rejuvenate CD8(+) tumor-infiltrating lymphocytes (TILs) and potentiate the effects of ICB and chemotherapy.