Tumour-specific CD8 T cells in solid tumours are dysfunctional, allowing tumours to progress. The epigenetic regulation of T cell dysfunction and therapeutic reprogrammability (for example, to immune checkpoint blockade) is not well understood. Here we show that T cells in mouse tumours differentiate through two discrete chromatin states: a plastic dysfunctional state from which T cells can be rescued, and a fixed dysfunctional state in which the cells are resistant to reprogramming. We identified surface markers associated with each chromatin state that distinguished reprogrammable from non-reprogrammable PD1hi dysfunctional T cells within heterogeneous T cell populations from tumours in mice; these surface markers were also expressed on human PD1hi tumour-infiltrating CD8 T cells. Our study has important implications for cancer immunotherapy as we define key transcription factors and epigenetic programs underlying T cell dysfunction and surface markers that predict therapeutic reprogrammability.
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We thank J. van der Veeken, V. Krisnawan, Y. Pritykin, and B. Gasmi for discussions and technical support; S. Reiner for discussions; and the MSKCC Flow Cytometry Core and Animal Facility. T.M., M.H., J.D.W., and A.S. are members of the Parker Institute for Cancer Immunotherapy. This work was supported by NIH-NCI grants R00 CA172371 (to A.S.), K08 CA158069 (to M.P.), and U54 CA209975 (to C.S.L. and A.S.), NHGRI grant U01 HG007893 (to C.S.L.), V Foundation for Cancer Research (to A.S.), the William and Ella Owens Medical Research Foundation (to A.S.), the Josie Robertson Young Investigator Award (to A.S.), and the MSKCC Core Grant P30 CA008748. The Integrated Genomics Operation Core was supported by Cycle for Survival and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology.
The authors declare no competing financial interests.
Reviewer Information Nature thanks J. Wherry and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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Extended data figures and tables
Extended Data Figure 1 Phenotypic and functional characteristics of naive TCRTAG CD8 T cells differentiating to effector and memory T cells during acute Listeria infection.
Naive TCRTAG cells (N; Thy1.1+) were transferred into B6 (Thy1.2+) mice, which were immunized with LmTAG one day later. At days 5, 7, and 60+ after LmTAG, effector (E5 and E7), and memory (M) T cells were isolated from spleens and assessed for phenotype and function. Flow cytometric analysis of CD44, CD62L, IL7Rα, TBET, and GZMB expression directly ex vivo (upper panel; inset numbers show MFI), and intracellular IFNγ and TNFα production and CD107 expression after 4 h of ex vivo TAG peptide stimulation (lower panel). Flow plots are gated on CD8+Thy1.1+ cells. For cytokine production, in grey are shown no-peptide control cells. (n = 8 total, with n = 2 per cell state). Each symbol represents an individual mouse. Data show mean ± s.e.m.; P values calculated using unpaired, two-tailed Student’s t-test. Data are representative of more than four independent experiments.
a, b, Plots are shown for all mouse (a) and human (b) CD8 T cell ATAC-seq samples displaying fragment length (bp; x axis) and read counts (y axis). (S1, S2, S3 represent replicates per sample group.)
a, ATAC-seq data reveals massive chromatin remodelling during normal CD8 T cell differentiation. MA plot of naive (N) and day 5 effectors (E5) showing log2 ratios of peak accessibility (E5/N) versus mean read counts for all atlas peaks. Significantly differentially accessible peaks are shown in red (FDR < 0.05). b, Epigenetic and transcriptional regulation of CD8 effector genes. ATAC-seq (left) and RNA-seq (right) signal profiles of Prf1 and Tnf in naive, effectors (E5 and E7), and memory (M) TCRTAG cells during acute LmTAG infection. c, d, Epigenetic and transcriptional regulation of early CD8 response genes in TCRTAG cells during acute listeria infection. Published expression data from the Immunological Genome Project (ref. 17; GSE15907) were used; early-response genes increase in expression within the first 12–24 h and late-response genes increase expression 24–48 h after naive T cells encounter LmOVA as determined in ref. 17. c, Cumulative distribution function of peak accessibility changes between N and E5. Peaks associated with early-response genes show fewer changes in accessibility as compared to peaks associated with late-response genes. The black line shows all peaks accessible in N or E5, the red line shows peaks associated with early-response genes and the blue line shows peaks associated with late-response genes. d, ATAC-seq signal profiles (left) and RNA expression (right) of the early response genes Ldha (top) and Mki67 (bottom) in N, E5/E7, and M TCRTAG cells during acute LmTAG infection (blue line; GSE89309, current data set) overlaid with expression data from ref. 17/Immunological Genome Project (red line).
Extended Data Figure 4 Chromatin peak accessibility changes during normal and dysfunctional CD8 T cell differentiation.
a, Number of DESeq-determined chromatin peak accessibility changes during each transition during normal CD8 T cell differentiation (Listeria infection) (right) and CD8 T cell differentiation to dysfunction during tumorigenesis (left) broken down by log2(FC) > 2, log2(FC) = 1–2, and log2(FC) < 1. b, Chromatin accessibility peaks gained or lost during normal and dysfunctional CD8 T cell differentiation were mainly found in intergenic and intronic regions. Pie charts showing the proportions of reproducible ATAC-seq peaks in exonic, intronic, intergenic, and promoter regions (left, distribution for all peaks in the atlas). Green box: normal CD8 T cell differentiation during LmTAG immunization; distribution for common and variably accessible peaks in N, E5, E7, and M functional CD8 T cells. Blue box: differentiation to dysfunction in progressing tumours; distribution for common and variably accessible peaks in N, L5, L7, L14, L21, L28, L35, and L60+. Variable: significant change in at least one cell type comparison (FDR < 0.05, log2(FC) > 1). Common: no change in any cell type comparison. c, Venn diagrams show the number of significantly changed peaks during the transition from naive (N) to day 5 effectors (E5) TCRTAG cells during acute listeria LmTAG infection versus N to L5 early malignant lesion-infiltrating TCRTAG cells (FDR < 0.05, log2(FC) > 2). Upper, Venn diagram shows opening peaks; lower, Venn diagram shows closing peaks. d, Selected biological process (BP) Gene Ontology (GO) terms enriched in peaks open in L5 relative to E5 as determined through GREAT analysis.
Extended Data Figure 5 NFATC1 targets become significantly more accessible during differentiation to dysfunction in early malignant lesions as compared to normal effector differentiation.
a, The 20 most significantly enriched transcription factor motifs in peaks opening (red) and closing (blue) between L5 and E5. b, Scatterplot comparing the changes in peak accessibility for all differentially accessible peaks containing the NFATC1 motif during the transition from naive (N) to day 5 effectors (E5) TCRTAG cells during acute listeria LmTAG infection versus N to L5 in pre-malignant lesions (FDR < 0.05, log2(FC) > 1). Highlighted are NFATC1 target peaks associated with genes encoding negative regulatory transcription factors and inhibitory receptors. Some genes, for example, Cblb and Klf4, had multiple NFATC1 target peaks, including peaks that decreased in accessibility. c, Genes with more accessible NFATC1 target peaks during differentiation to dysfunction in malignant lesions show increased expression levels. Gene expression for genes with peaks in sector 1 and sector 2, with increased and decreased accessibility in L5 versus E5, respectively. Heat maps show RNA-seq expression data (row-normalized) for differentially expressed (P < 0.01, log2(FC) > 1) genes with NFATC1 target peaks contained in sector 1 (red box) or sector 2 (blue box) of scatterplot presented b. The majority of sector 1 genes (195 out of 223, 87%) revealed increased expression in dysfunctional TST as compared to E5, whereas the majority of sector 2 genes (21 out of 33, 63%) had decreased expression. Genes are clustered by row according to expression across the samples. Interestingly, although many genes in sector 1 had transiently increased expression in L5 and L7 (red box, upper left), many genes increased in expression at later stages of tumorigenesis at L14 and beyond (red box, upper right). This suggests that NFATC1 activation of downstream targets (negative regulators of T cell function) may not only induce early dysfunction, but may cause or contribute to the transition from plastic to fixed dysfunction.
a, Transcription factor footprinting in chromatin accessible regions. ATAC cut site distributions show footprints for CTCF, LEF1, NFATC1, and TCF7 in naive CD8 T cells. Shown is the mean number of ATAC cut sites on the forward (red) or reverse (blue) strand 100 bp up and downstream of the transcription factor motif site, calculated for atlas peaks predicted by FIMO to be bound by the respective transcription factor (P < 10−4). b, TCF1 expression (MFI; mean fluorescence intensity). Each symbol represents individual mouse. Mean ± s.e.m. shown; ***P ≤ 0.0001 (Student’s t-test). c, Selected biological processes (BP) (gene ontology (GO) terms) enriched in genes which significantly lost chromatin accessibility during the L7 to L14 transition as determined through GREAT analysis. d, Gain and losses of regulatory elements for top 50 most differentially expressed genes associated with TCR signalling during the L7 to L14 transition. Top 25 genes associated with TCR signalling with highest and lowest logFC gene expression changes are shown. Each gene is illustrated by a stack of diamonds, where each diamond represents a chromatin peak associated with the gene. Red diamonds denote peaks gained in the transition, blue diamonds denote peaks that were lost.
Extended Data Figure 7 Pharmacological targeting of NFAT and Wnt/β-catenin signalling prevents TST differentiation to the fixed dysfunctional state in vivo.
a, Experimental scheme. Naive TCRTAG cells (Thy1.1+) were transferred into AST-Cre-ERT2 (Thy1.2+) mice which were treated with tamoxifen (tam) one day later. At days 2–9 mice were treated with the calcineurin inhibitor FK506 (2.5 mg kg−1 per mouse) alone (FK506 treatment group; orange), or in combination with the GSK3β inhibitor TWS119 (0.75 mg per mouse; days 5–8) (FK506 + TWS119 treatment group; green), or PBS/DMSO (control group; blue) as indicated. At day 10, TCRTAG cells were isolated from livers and assessed for phenotype and function. b, Flow cytometric analysis of CD44, PD1, LAG3, TCF1, and EOMES expression of TCRTAG cells. c, Production of IFNγ and TNFα by TCRTAG cells isolated at day 10 (left panel; ex vivo), and after 3 days IL-15 in vitro culture (right panel). Each symbol represents an individual mouse. Data show mean ± s.e.m.; P values calculated using unpaired two-tailed t-test. d, Representative flow cytometric analysis of CD38 and CD101 expression of TCRTAG cells (numbers indicate %); CD38, CD101 and CD5 expression. Each symbol represents an individual mouse. Data show mean ± s.e.m.; P values calculated using unpaired two-tailed t-test. These data are representative of 2 independent experiments (with total n = 10 for experiment 1; n = 9, experiment 2).
Extended Data Figure 8 Epigenetic and expression dynamics of membrane proteins and transcription factors associated with T cell dysfunction.
a, ATAC-seq signal profile across the Cd38 loci with ‘state 2’ uniquely accessible peaks highlighted in pink; activation-associated peaks highlighted in blue. b, Expression profiles of N, L5, L7, L14, and L60+ TCRTAG cells for CD101 versus CD38, TCF versus PD1, and TCF1 versus CD38 by flow cytometric analysis. c, Expression of transcription factors and other proteins on tumour-specific TCRTAG T cells over the course of tumorigenesis (MFI; mean fluorescence intensity). Each symbol represents an individual mouse. Data shows mean ± s.e.m. (bottom panel). Representative flow histogram overlays are shown. d–f, TCROT1 TST in established B16-OVA tumours enter plastic and fixed dysfunctional states. d, Immunophenotype of and cytokine production by TCROT1 cells re-isolated from established B16-OVA tumours 5 (D5) and 13 (D13) days after transfer. e, CD38, CD101 and CD5 expression on day 5 and day 13 TCROT1 cells. f, Cytokine production by day 5 and day 21 TCROT1 cells after 3 days of IL-15 in vitro culture. Each symbol represents individual mouse. Mean ± s.e.m. shown; *P = 0.03, **P = 0.002, ***P ≤ 0.0003 (Student’s t-test).
Extended Data Figure 9 Chromatin state dynamics of memory TCRTAG cells differentiating to the dysfunctional state in solid tumours.
a, PD1 and LAG3 expression and cytokine production of memory TCRTAG cells in liver tumours. Each symbol represents individual mouse. Mean ± s.e.m. shown; *P = 0.03, **P = 0.006, ***P < 0.0001 (Student’s t-test); representative of four independent experiments. b, Numbers of ATAC-seq peaks significantly opening or closing (FDR < 0.05) during each transition as memory TCRTAG cells differentiate to the dysfunctional state 7, 14, and 35 days after transfer into hepatocellular-carcinoma-tumour bearing AST-Alb-Cre mice with ((+); left) and without ((−); right) listeria LmTAG immunization; peaks opening (red), peaks closing (blue). c, Principal component analysis of peak accessibility during naive TCRTAG cells differentiation in acute infection (green), early tumorigenesis (blue), and memory TCRTAG cells in established hepatocellular carcinomas (red). Circles, with LmTAG immunization; diamonds, no LmTAg immunization. d, Chromatin accessibility heat map. Each row represents 1 of 11,698 selected peaks (differentially accessible between any sequential cell comparison; FDR < 0.05, log2(FC) > 2). Shown are ±1 kb from the peak summit (2 kb total per region). e, ATAC-seq signal profiles of Pdcd1, Ctla4, Cd38, Tcf7, and Ifng genes of naive (N; grey), memory (M; green), L7, L14, L35 (blue series), and ML7, ML14, and ML35 (red series) TCRTAG cells. Pink boxes highlight peaks that become accessible in dysfunctional T cells compared to naive and memory; blue boxes highlight peaks that become inaccessible in dysfunctional TCRTAG cells compared to naive and memory TCRTAG cells. f, CD38, CD101, CD30L, and CD5 expression on ML7, ML14, ML21. Inset numbers show MFI.
Extended Data Figure 10 Chromatin states of human PD1hi tumour-infiltrating CD8+ T cells and model for CD8 TST differentiation and dysfunction in tumours.
a, Sorting scheme of peripheral blood lymphocytes for naive (N), effector memory (EM), central memory (CM) CD8 T cell populations (left), and PD1hi CD8 TIL from patients with melanoma or non-small-cell lung cancer. b, Differentially accessible ATAC-seq peaks grouped by DESeq-defined differential accessibility pattern. Each column represents one biological replicate. Samples shown include CD45RA+CD45RO− (naive; grey), CD45RA−CD45RO+CD62L− (effector memory; light green) and CD45RA−CD45RO+CD62L+ (central memory; dark green) peripheral blood CD8+ T cells from healthy donors, and CD45RA−CD45RO+PD1hiCD8+ T cells isolated and flow-sorted from human melanoma and lung tumours (PD1hi TIL; blue). Open, accessible chromatin regions are presented in red; inaccessible chromatin regions are presented in blue. c, ATAC-seq signal profiles of SELL in naive, effector memory, and central memory. Blue boxes highlight peaks that remain accessible in central memory or become inaccessible in effector member compared to naive respectively. d, ATAC-seq signal profiles of IFNG, EGR2, CD5, and CTLA4. Pink and blue boxes highlight peaks that become accessible or inaccessible in PD1hi TIL compared to naive or central memory, respectively. e, Model for tumour-specific CD8 T cell differentiation and dysfunction in tumours.
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Philip, M., Fairchild, L., Sun, L. et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 545, 452–456 (2017). https://doi.org/10.1038/nature22367
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