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

被引：53

作者：

Bae, Joonbeom ^{[1
]}

Liu, Longchao ^{[1
]}

Moore, Casey ^{[1
,2
]}

Hsu, Eric ^{[1
,2
]}

Zhang, Anli ^{[1
]}

Ren, Zhenhua ^{[1
]}

Sun, Zhichen ^{[1
,3
]}

Wang, Xue ^{[1
]}

Zhu, Jiankun ^{[1
]}

Shen, Jiao ^{[4
,5
]}

Qiao, Jian ^{[1
]}

Fu, Yang-Xin ^{[1
,6
]}

机构：

[1] Univ Texas Southwestern Med Ctr, Dept Pathol, Dallas, TX 75390 USA

[2] Univ Texas Southwestern Med Ctr, Dept Immunol, Dallas, TX USA

[3] Univ Texas Southwestern Med Ctr, Harold C Simmons Comprehens Canc Ctr, Dept Pharmacol, Dallas, TX USA

[4] Chinese Acad Sci, Inst Biophys, Key Lab Infect & Immun, Beijing, Peoples R China

[5] Univ Chinese Acad Sci, Beijing, Peoples R China

[6] Tsinghua Univ, Sch Med, Dept Basic Med Sci, Beijing, Peoples R China

来源：

NATURE CELL BIOLOGY | 2022年 / 24卷 / 12期

关键词：

DIFFERENTIATION; EXHAUSTION; TUMORS; NK-92;

D O I：

10.1038/s41556-022-01024-5

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1754 / 1765

页数：33

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