Discovery of Tcf7 regulators with clonally-resolved CRISPR screens identifies Trim28 as a mediator of CD8 T cell differentiation in tumors
Schwartz, M. A.; Lue, D.; Mutaher, M.; McNerney, M.; Olajide, O.; Mehta, A.; Rowe, J. H.; Park, R. J.; Malehmir, M.; Dubrot, J.; Al'Khafaji, A. M.; Bakalar, M.; Bi, L.; LaFleur, M. W.; Yates, K. B.; Manguso, R. T.; Doench, J. G.; Sharpe, A. H.; Pritykin, Y.; Hacohen, N.
Show abstract
Stem-like TCF7+ CD8 T cells sustain anti-tumor responses and support immune checkpoint blockade. We systematically identified regulators of this cell state using genome-wide CRISPR screens in primary T cells in vitro. Using random barcodes to link clonal relationships with guide identity and transcriptional states in single cells, we inferred differentiation trajectories and differentiation rates of CD8 T cells in tumors, while mitigating confounding clonal bias. We found that Trim28-deficient T cells in tumors were enriched in the TCF7+ cell state, depleted in cycling and terminal effector states, and uniquely generated a tissue-resident memory (TRM)-like state with increased chromatin accessibility at known TRM loci as well as repeat elements. Despite the increase in TCF7+ CD8 T cells, loss of Trim28 did not improve tumor control, likely because of reduced effector differentiation, highlighting the need for tuning the balance and dynamics of stem-like versus effector states for effective tumor clearance.
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