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Discovery of Tcf7 regulators with clonally-resolved CRISPR screens identifies Trim28 as a mediator of CD8 T cell differentiation in tumors

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 generating 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE334890 | GEO | 2026/07/09

REPOSITORIES: GEO

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Discovery of Tcf7 regulators with clonally-resolved CRISPR screens identifies Trim28 as a mediator of CD8 T cell differentiation in tumors [CRISPR Screen]

Project description: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 generating 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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Discovery of Tcf7 regulators with clonally-resolved CRISPR screens identifies Trim28 as a mediator of CD8 T cell differentiation in tumors [Multiome]

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Discovery of Tcf7 regulators with clonally-resolved CRISPR screens identifies Trim28 as a mediator of CD8 T cell differentiation in tumors [RNA-Seq]

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GZMK-expressing tissue-resident memory CD8+ T cells mediate human intestinal acute graft-versus-host disease [INT]

Project description:Tissue-resident memory T cells (TRM) have recently emerged as crucial cellular players for murine acute graft-versus-host disease (aGVHD) development. However, the role of distinct subsets of CD8+TRM cells in human intestinal aGVHD is not well known yet. Herein,we combined multiplex immunohistochemical staining with single-cell RNA sequencing to elucidate the differentiation trajectory, lineage commitment, clonal expansion and functional properties of distinct CD8+TRM cell subsets in human intestinal aGVHD. We revealed seven functionally distinct CD8+TRM subsets and innovatively uncovered a significant GZMK+CD8+TRM subset. GZMK+CD8+TRM subset mediated human intestinal aGVHD by exhibiting enhanced clonal expansion, IFN signaling pathway-associated proinflammatory, and lineage bifurcation differentiation properties. High GZMK+CD8+TRM subset infiltration is correlated with human intestinal aGVHD severity and poor prognosis. Therefore, we demonstrated that human intestinal aGVHD is in good part mediated by pivotal GZMK+CD8+TRM subset. Targeting key CD8+TRM cell subsets could be a new treatment approach in the human intestinal aGVHD.

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GZMK-expressing tissue-resident memory CD8+ T cells mediate human intestinal acute graft-versus-host disease

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Single cell analysis of epidermis from nickel-challenged skin

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Project description:DNMT3a is a de novo DNA methyltransferase expressed robustly after T cell activation that regulates plasticity of CD4+ T cell cytokine expression. Here we show that DNMT3a is critical for directing early CD8+ T cell effector and memory fate decisions. While effector function of DNMT3a knockout T cells is normal, they develop more memory precursor and fewer terminal effector cells in a T cell intrinsic manner compared to wild-type animals. Rather than increasing plasticity of differentiated effector CD8+ T cells, loss of DNMT3a biases differentiation of early effector cells into memory precursor cells. This is attributed in part to ineffective repression of Tcf1 expression in knockout T cells, as DNMT3a localizes to the Tcf7 promoter and catalyzes its de novo methylation in early effector WT CD8+ T cells. This data identifies DNMT3a as a crucial regulator of CD8+ early effector cell differentiation and effector versus memory fate decisions. Examination of global genomic DNA methylation by MBD-seq in naÃ¯ve CD8 T cells and CD8 T cells 8 days post Vaccinia-Ova infection, comparing OT1 TCR-Tg CD8 T cells isolated from WT and T cell conditional DNMT3a KO mice.

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Distinct CD8+ T cell dynamics associate with response to neoadjuvant cancer immunotherapies

Project description:We leverage a clinical trial (NCT04080804) that compared neoadjuvant anti-PD-1, anti-PD-1+CTLA-4, and anti-PD-1+LAG-3 therapies in head and neck squamous cell carcinoma patients. Combination therapies promote higher pathologic response rates versus monotherapy, and major pathologic response is associated with better survival. To address whether successful immune checkpoint inhibitor (ICI) regimens act through similar or distinct pathways, we robustly and longitudinally characterize transcriptional and proteomic dynamics of CD8+ tumor-infiltrating lymphocytes (TILs) in a clonal manner. Anti-PD-1+LAG-3 reprograms CD8+ TIL with type-I interferon response and exhaustion gene programs into effector memory and resident memory (TEM/TRM). In contrast, anti-PD-1+CTLA-4 activates and expands pre-existing TEM/TRM CD8+ TIL, but does not rejuvenate exhausted phenotypes into T effector cells. Anti-PD-1+LAG-3, but not anti-PD-1+CTLA-4, induces widespread TCR sharing among the different transcriptional states, as well as increased TCR diversity in responding patients. Our data suggest doublet regimen-specific transcriptional and clonal dynamics of tumor-reactive CD8+ T cells.

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Project description:The transcription factor (TF) networks that regulate the differentiation of resident versus circulating memory CD8+ T cells are incompletely understood. Here we show that the TF Bcl11b restricts gut resident memory (Trm) cell differentiation, while promoting splenic T central memory (Tcm) and effector memory (Tem) cell differentiation. The reduction of Bcl11b-deficient splenic Tcm and Tem cells was not due to major alterations in their programs, but rather due to the increased homing of their precursors to the small intestine. However, Bcl11b-deficient resident memory precursor cells upregulated residency program, including the TFs Ahr and Prdm1 (encoding Blimp1), and downregulated Tcf7, which restricts the residency program and promotes tissue egress. Bcl11b directly bound at Ahr and Prdm1, as well as at Tcf7 genes. Abrogating Ahr and Prdm1, or restoration of Tcf7 expression in Bcl11b-deficient cells led to partial correction of the excessive resident memory cell differentiation. Functionally, Bcl11b-deficient memory CD8+ T cells had an impaired recall response, but anti-tumor immunity was increased in adoptive cell therapy. Bcl11b also repressed the residency program in human CD8+ T cells and human Bcl11b low tumor-infiltrating lymphocytes showed increased residency gene expression. Thus, Bcl11b plays a critical role in balancing the circulating and tissue residency programs and reveals a potential novel target for cancer immunotherapies.

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