Ao Guo  ^# 1,  Hongling Huang  ^# 1,  Zhexin Zhu ²,  Mark J Chen ¹,  Hao Shi ¹,  Sujing Yuan ¹,  Piyush Sharma ¹,  Jon P Connelly ³,  Swantje Liedmann ¹,  Yogesh Dhungana ¹,  Zhenrui Li ¹,  Dalia Haydar ⁴,  Mao Yang ¹,  Helen Beere ¹,  Jason T Yustein ⁵,  Christopher DeRenzo ⁴,  Shondra M Pruett-Miller ³,  Jeremy Chase Crawford ¹,  Giedre Krenciute ⁴,  Charles W M Roberts ²,  Hongbo Chi ⁶,  Douglas R Green ⁷

Affiliations

• 1Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.
• 2Comprehensive Cancer Center and Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
• 3Center for Advanced Genome Engineering, St Jude Children's Research Hospital, Memphis, TN, USA.
• 4Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, TN, USA.
• 5Baylor Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
• 6Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. hongbo.chi@stjude.org.
• 7Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. douglas.green@stjude.org.
• #Contributed equally.

PMID: 35732731   DOI: 10.1038/s41586-022-04849-0

Abstract

The identification of mechanisms to promote memory T (T_mem) cells has important implications for vaccination and anti-cancer immunotherapy^1-4. Using a CRISPR-based screen for negative regulators of T_mem 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 (T_eff) cells, and their loss promotes T_mem 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 T_eff cells, whereas those with low MYC and low cBAF preferentially differentiate towards T_mem 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 T_mem cell fate and suggest that manipulation of cBAF early in T cell differentiation can improve Cancer Immunotherapy.