IL-4 drives exhaustion of CD8+ CART cells

被引：8

作者：

Stewart, Carli M. ^{[1
,2
,3
]}

Siegler, Elizabeth L. ^{[1
,4
]}

Sakemura, R. Leo ^{[1
,4
]}

Cox, Michelle J. ^{[1
]}

Huynh, Truc ^{[1
,4
]}

Kimball, Brooke ^{[1
,4
]}

Mai, Long ^{[1
,4
]}

Can, Ismail ^{[1
,4
]}

Roman, Claudia Manriquez ^{[1
]}

Yun, Kun ^{[1
,2
,5
]}

Sirpilla, Olivia ^{[1
,2
,3
]}

Girsch, James H. ^{[1
,2
,5
]}

Ogbodo, Ekene ^{[1
,4
]}

Ismail, Wazim Mohammed ^{[6
]}

Gaspar-Maia, Alexandre ^{[6
]}

Budka, Justin ^{[7
]}

Kim, Jenny ^{[7
]}

Scholler, Nathalie ^{[7
]}

Mattie, Mike ^{[7
]}

Filosto, Simone ^{[7
]}

Kenderian, Saad S. ^{[1
,4
,8
]}

机构：

[1] Mayo Clin, T Cell Engn, Rochester, MN 55905 USA

[2] Mayo Clin, Grad Sch Biomed Sci, Rochester, MN USA

[3] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN USA

[4] Mayo Clin, Div Hematol, Rochester, MN 55905 USA

[5] Mayo Clin, Dept Mol Med, Rochester, MN USA

[6] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA

[7] Gilead Sci Inc, Dept Oncol, Foster City, CA USA

[8] Mayo Clin, Dept Immunol, Rochester, MN 55905 USA

来源：

NATURE COMMUNICATIONS | 2024年 / 15卷 / 01期

基金：

美国国家卫生研究院;

关键词：

T-CELLS; TRANSCRIPTION; ALPHA; BATF; JUN;

D O I：

10.1038/s41467-024-51978-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Durable response to chimeric antigen receptor T (CART) cell therapy remains limited in part due to CART cell exhaustion. Here, we investigate the regulation of CART cell exhaustion with three independent approaches including: a genome-wide CRISPR knockout screen using an in vitro model for exhaustion, RNA and ATAC sequencing on baseline and exhausted CART cells, and RNA and ATAC sequencing on pre-infusion CART cell products from responders and non-responders in the ZUMA-1 clinical trial. Each of these approaches identify interleukin (IL)-4 as a regulator of CART cell dysfunction. Further, IL-4-treated CD8+ CART cells develop signs of exhaustion independently of the presence of CD4+ CART cells. Conversely, IL-4 pathway editing or the combination of CART cells with an IL-4 monoclonal antibody improves antitumor efficacy and reduces signs of CART cell exhaustion in mantle cell lymphoma xenograft mouse models. Therefore, we identify both a role for IL-4 in inducing CART exhaustion and translatable approaches to improve CART cell therapy.

引用

页数：17

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