cBAF complex components and MYC cooperate early in CD8+ T cell fate

Ao Guo, Hongling Huang, Zhexin Zhu, Mark J. Chen, Hao Shi, Sujing Yuan, Piyush Sharma, Jon P. Connelly, Swantje Liedmann, Yogesh Dhungana, Zhenrui Li, Dalia Haydar, Mao Yang, Helen Beere, Jason T. Yustein, Christopher DeRenzo, Shondra M. Pruett-Miller, Jeremy Chase Crawford, Giedre Krenciute, Charles W. M. Roberts, Hongbo Chi () and Douglas R. Green ()
Additional contact information
Ao Guo: St Jude Children’s Research Hospital
Hongling Huang: St Jude Children’s Research Hospital
Zhexin Zhu: St Jude Children’s Research Hospital
Mark J. Chen: St Jude Children’s Research Hospital
Hao Shi: St Jude Children’s Research Hospital
Sujing Yuan: St Jude Children’s Research Hospital
Piyush Sharma: St Jude Children’s Research Hospital
Jon P. Connelly: St Jude Children’s Research Hospital
Swantje Liedmann: St Jude Children’s Research Hospital
Yogesh Dhungana: St Jude Children’s Research Hospital
Zhenrui Li: St Jude Children’s Research Hospital
Dalia Haydar: St Jude Children’s Research Hospital
Mao Yang: St Jude Children’s Research Hospital
Helen Beere: St Jude Children’s Research Hospital
Jason T. Yustein: Texas Children’s Hospital, Baylor College of Medicine
Christopher DeRenzo: St Jude Children’s Research Hospital
Shondra M. Pruett-Miller: St Jude Children’s Research Hospital
Jeremy Chase Crawford: St Jude Children’s Research Hospital
Giedre Krenciute: St Jude Children’s Research Hospital
Charles W. M. Roberts: St Jude Children’s Research Hospital
Hongbo Chi: St Jude Children’s Research Hospital
Douglas R. Green: St Jude Children’s Research Hospital

Nature, 2022, vol. 607, issue 7917, 135-141

Abstract: Abstract The identification of mechanisms to promote memory T (Tmem) cells has important implications for vaccination and anti-cancer immunotherapy1–4. Using a CRISPR-based screen for negative regulators of Tmem cell generation in vivo5, here we identify multiple components of the mammalian canonical BRG1/BRM-associated factor (cBAF)6,7. Several components of the cBAF complex are essential for the differentiation of activated CD8+ T cells into T effector (Teff) cells, and their loss promotes Tmem cell formation in vivo. During the first division of activated CD8+ T cells, cBAF and MYC8 frequently co-assort asymmetrically to the two daughter cells. Daughter cells with high MYC and high cBAF display a cell fate trajectory towards Teff cells, whereas those with low MYC and low cBAF preferentially differentiate towards Tmem cells. The cBAF complex and MYC physically interact to establish the chromatin landscape in activated CD8+ T cells. Treatment of naive CD8+ T cells with a putative cBAF inhibitor during the first 48 h of activation, before the generation of chimeric antigen receptor T (CAR-T) cells, markedly improves efficacy in a mouse solid tumour model. Our results establish cBAF as a negative determinant of Tmem cell fate and suggest that manipulation of cBAF early in T cell differentiation can improve cancer immunotherapy.

Date: 2022
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DOI: 10.1038/s41586-022-04849-0

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