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Single-cell CRISPR screens in vivo map T cell fate regulomes in cancer
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Journal Article
Single-cell CRISPR screens in vivo map T cell fate regulomes in cancer
2023
Overview
CD8
+
cytotoxic T cells (CTLs) orchestrate antitumour immunity and exhibit inherent heterogeneity
1
,
2
, with precursor exhausted T (T
pex
) cells but not terminally exhausted T (T
ex
) cells capable of responding to existing immunotherapies
3
–
7
. The gene regulatory network that underlies CTL differentiation and whether T
ex
cell responses can be functionally reinvigorated are incompletely understood. Here we systematically mapped causal gene regulatory networks using single-cell CRISPR screens in vivo and discovered checkpoints for CTL differentiation. First, the exit from quiescence of T
pex
cells initiated successive differentiation into intermediate T
ex
cells. This process is differentially regulated by IKAROS and ETS1, the deficiencies of which dampened and increased mTORC1-associated metabolic activities, respectively. IKAROS-deficient cells accumulated as a metabolically quiescent T
pex
cell population with limited differentiation potential following immune checkpoint blockade (ICB). Conversely, targeting ETS1 improved antitumour immunity and ICB efficacy by boosting differentiation of T
pex
to intermediate T
ex
cells and metabolic rewiring. Mechanistically, TCF-1 and BATF are the targets for IKAROS and ETS1, respectively. Second, the RBPJ–IRF1 axis promoted differentiation of intermediate T
ex
to terminal T
ex
cells. Accordingly, targeting RBPJ enhanced functional and epigenetic reprogramming of T
ex
cells towards the proliferative state and improved therapeutic effects and ICB efficacy. Collectively, our study reveals that promoting the exit from quiescence of T
pex
cells and enriching the proliferative T
ex
cell state act as key modalities for antitumour effects and provides a systemic framework to integrate cell fate regulomes and reprogrammable functional determinants for cancer immunity.
Analyses of causal gene regulatory networks have identified key checkpoints mediating the progressive differentiation of CD8
+
cytotoxic T cells, findings that have implications for anticancer immunotherapies such as adoptive cell therapy and immune checkpoint blockade.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 45/61
/ 45/91
/ 96
/ 96/31
/ Cancer
/ Cell Differentiation - drug effects
/ Cell Differentiation - genetics
/ Cells
/ Clustered Regularly Interspaced Short Palindromic Repeats - genetics
/ CRISPR
/ Humanities and Social Sciences
/ Humans
/ Immune checkpoint inhibitors
/ Immune Checkpoint Inhibitors - immunology
/ Immune Checkpoint Inhibitors - pharmacology
/ Immunity
/ Science
/ Single-Cell Analysis - methods
/ T-Lymphocytes, Cytotoxic - cytology
/ T-Lymphocytes, Cytotoxic - drug effects
