Bae, Liu, and Moore et al. showed that as murine tumors progressed, CD8+ TILs exhibited exhaustion markers and decreased signaling by IL-2, which was essential for anti-PD-L1 response. Tumor-tropic mesenchymal stem cells (MSCs) were engineered to express an IL-2 mutein controlled by a hypoxia-induced promoter to minimize systemic toxicity, and to overexpress an oxidoreductase to improve MSC TME survival and sensitize cells to β-lapachone-mediated killing. Treating mouse tumor models with the MSCs revitalized pre-existing CD8+ TILs, boosted local and abscopal antitumor responses, reversed resistance to anti-PD-L1 and chemotherapy, and induced immune memory.
Contributed by Paula Hochman
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 Info: (1) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (2) Department of Pathology, University of Texas Southwestern Medical Center, Dallas,
Author Info: (1) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (2) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (3) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (4) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (5) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (6) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (7) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Department of Pharmacology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. (8) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (9) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (10) Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. University of Chinese Academy of Sciences, Beijing, China. (11) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Jian.Qiao@UTSouthwestern.edu. (12) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. yangxinfu@tsinghua.edu.cn. Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China. yangxinfu@tsinghua.edu.cn.
