The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
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Battistello, E., Hixon, K.A., Comstock, D.E. et al. Molecular Cell. 83(8): 1216-1236 (2023).
doi: 10.1016/j.molcel.2023.02.026.
**Summary, future impact and graphical abstract by Alexandra Boitor**
Summary of the findings
T-cell activation and exhaustion are underlined by changes in gene expression. Whilst several transcription factors involved in this process have been identified, the regulatory mechanisms of the T-cell activation state are not fully understood. In their paper, Battistello, Hixon, Comstock et all characterised these changes in gene expression and the mechanisms by which such changes are regulated, with a focus on mSWI/SNF.
Comprehensive profiling of genome-wide occupancy revealed increases in histone peaks and total mSWI/SNF occupancy at T cell activation. Chromatin accessibility and mSWI/SNF occupancy steadily decrease from T-cell early activation to late activation and exhaustion, with progressively fewer mSWI/SNF-bound sites characterising the accessible chromatin. Each state is also characterised by the binding of specific transcription factors and stepwise changes in gene expression. Gene loci for differentially upregulated genes between T-cell activation states are increasingly occupied by mSWI/SNF complexes from T-cell activation (23% of upregulated loci) to exhaustion (40%), highlighting an important role for mSWI/SNF in controlling transcriptional processes responsible for T-cell exhaustion. Depletion of any components of the mSWI/SNF complex in vitro leads to increased T-cell persistence and a slight increase in the number of T-cells that present a memory-like phenotype further highlighting the important role the mSWI/SNF complexes play in T-cell exhaustion.
Future impact
Pharmacological perturbations of the mSWI/SNF complex by using small-molecule allosteric inhibitors of SMARCA4/2 ATPase activity or degraders of SMARCA4/2 ATPase subunit has the ability to attenuate T-cell activation status and thus inhibit T-cell exhaustion and promote the proliferative memory-like state by modulating chromatin accessibility. This is particularly relevant in the context of CAR-T therapy, as CAR-Ts with increased persistence are believed to exhibit enhanced anti-tumour activity.
