Abstract
Cryptic promoters within transposable elements (TEs) can be transcriptionally reactivated in tumors to create new TE-chimeric transcripts, which can produce immunogenic antigens. We performed a comprehensive screen for these TE exaptation events in 33 TCGA tumor types, 30 GTEx adult tissues and 675 cancer cell lines, and identified 1,068 TE-exapted candidates with the potential to generate shared tumor-specific TE-chimeric antigens (TS-TEAs). Whole-lysate and HLA-pulldown mass spectrometry data confirmed that TS-TEAs are presented on the surface of cancer cells. In addition, we highlight tumor-specific membrane proteins transcribed from TE promoters that constitute aberrant epitopes on the extracellular surface of cancer cells. Altogether, we showcase the high pan-cancer prevalence of TS-TEAs and atypical membrane proteins that could potentially be therapeutically exploited and targeted.
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Data availability
All sequencing and mass spectrometry data generated in this study are available at the following accession codes (GEO accession code: GSE201021; PRIDE code: PXD033351). Links and accession codes to all publicly available data used in this study are detailed in Methods section. Source data are provided with this paper.
Code availability
TEProF2, the custom pipeline used to identify TE-chimeric transcripts from RNA-sequencing data, is available with the following link: https://doi.org/10.5281/zenodo.7670515. All other codes used to generate the analysis and figures have been placed in a notebook that is made available through the following link: https://doi.org/10.5281/zenodo.7670584. Source data are provided with this paper.
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Acknowledgements
We would like to thank Z. Andrysik and J.M. Espinosa from the Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA, for the generous gift of TP53-KO HCT116 cell line. We would like to thank J. Hoisington-López and M.L. Jaeger from The Edison Family Center for Genome Sciences & Systems Biology (CGSSB) for assistance with sequencing and B. Koebbe and E. Martin from CGSSB for data processing. T.W. is funded by NIH grants 5R01HG007175, U24ES026699 and U01HG009391 and the American Cancer Society Research Scholar grant number RSG- 14-049-01-DMC awarded. N.M.S. was a Howard Hughes Medical Institute (H.H.M.I.) Medical Research Fellow. H.J.J. was supported by a grant from NIGMS (T32 GM007067). The LC–MS/MS work from the Proteomics & Mass Spectrometry Facility at the Danforth Plant Science Center is supported by National Science Foundation grant DBI-1827534 for the acquisition of the Orbitrap Fusion Lumos LC–MS/MS.
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Contributions
N.M.S., H.J.J. and T.W. conceived and implemented the study; N.M.S., J.M., A.W., C.F., B.K., D.L. and T.W. contributed to the computational analysis; N.M.S. developed the computational pipeline to search for tumor-specific TE-chimeric transcripts; N.M.S. and J.M. analyzed the CAGE and the ATAC-seq data. N.M.S. and C.F. analyzed the methylation array data. N.M.S., A.W. and Y.L. processed the whole-lysate, HLA-pulldown and synthetic peptide LC–MS/MS datasets. H.J.J., J.M. and X.X. generated transcriptomic profiles of cell lines; H.J.J. and Y.L. performed membrane extraction and Western blot analysis; H.J.J., N.L.B. and Y.L. maintained and collected cell lines for LC–MS; H.J.J. performed the HLA-pulldown; Y.L. and X.Q. performed TP53 HCT116 experiments; Y.L. performed immunofluorescence experiments; Y.L. and A.L. performed targeted IP-LC–MS/MS experiments; S.-C.T. and B.S.E. performed the LC–MS/MS; and the paper was prepared and revised by N.M.S., H.J.J., Y.L. and T.W. with input from all authors.
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Extended data
Extended Data Fig. 1 Expression of TE-chimeric transcripts across TCGA and GTEx.
a, Frequency of 26,816 TE-chimeric transcripts in 33 cancer types from TCGA. Each dot represents a separate sample, and the top of the graph lists the number of samples in each cancer type and the mean number of TE-chimeric transcripts for that cancer type. b, Same as (a) but with TCGA normal tissue samples. c, Same as (a) but with GTEx adult tissue samples. d, For tumors with matched normal samples in TCGA, box plots of the number of TE-chimeric transcripts across all samples. There is a superimposed dot plot with a line connecting matched tumor and normal samples. The ‘N=’ lists the number of samples summarized with the box plots. All box plots follow the following format: center line, median; box limits, upper and lower quartiles; whiskers, 1.5x interquartile range.
Extended Data Fig. 2 Epigenetic Correlations and Filtering with TCGA, GTEx, and FANTOM5 samples.
a, Spearman rho correlation of global methylation versus number of all 26,816 TE-chimeric transcripts across cancer types and all samples. Purple bars represent significant correlations (Adjusted P-value < 0.05). Exact p-values are the following: STAD: 2.93E-04, HNSC: 1.27E-05, LUSC: 1.58E-03, BLCA: 2.33E-02, UCEC: 3.20E-02, KIRP: 1.23E-01, SKCM: 5.73E-02, LUAD: 2.65E-01, READ: 6.69E-01, LIHC: 2.65E-01, KIRC: 4.47E-01, PCPG: 6.69E-01, ESCA: 8.485E-01, LGG: 6.69E-01, PAAD: 8.48E-01, COAD: 8.48E-01, SARC: 8.72E-01, BRCA: 8.66E-01, PRAD: 9.22E-01, CESC: 9.22E-01, THCA: 6.69E-01, All: 9.24E-01. b, Dot plot of difference in number of all TE-chimeric transcripts between samples that have a particular driver mutation and those that do not in a specific cancer type. Dots are ordered by difference. Wilcoxon rank sum test (two-sided) was used with Benjamin-Hochberg correction. Exact o-values for significant differences are the following: COAD-APC: 1.17E-03, COAD-TP53: 3.15E-06, READ-TP53: 9.01E-04, STAD-TP53: 3.70E-02, HNSC-CASP8: 7.80E-04, HNSC-NOTCH1: 4.37E-02, HNSC-NSD1: 3.08E-04, BRCA-TP53: 4.37E-02, LIHC-TP53: 7.11E-03. c, Number of tumor and normal samples all TE-chimeric transcripts were present in. Those highlighted in blue passed our threshold for tumor-specificity. The bottom graph is a zoomed in on the section of the top graph that has a dotted box around it. d, Number of TCGA tumor and GTEx adult normal samples all TE-chimeric transcripts were present in. Those highlighted in blue passed our threshold for tumor-specificity. e, Number of samples in each tissue type profiled by FANTOM5. f, Expression of candidate promoters in FANTOM5. Dashed box highlights candidates removed due to high expression in adult tissues.
Extended Data Fig. 3 Summary statistics for TE-chimeric transcripts.
a, Scatter plot of the mean fraction of the target gene’s expression a chimeric transcript accounts for and the number of tumor samples where the transcript is present. Box plot format: center line, median; box limits, upper and lower quartiles; whiskers, 1.5x interquartile range; points, outliers. b, TE class distribution and enrichment of tumor-specific TE-chimeric transcripts. The size of the dot represents the number of TE-chimeric transcripts belonging to that class. c, TE subfamily number and enrichment of candidates.
Extended Data Fig. 4 Association of TE-chimeric transcripts with methylation, chromatin accessibility, and driver mutations.
a, Scatter plot of global methylation versus number of candidates across samples in 21 tumor types. The regression line is plotted, and the Spearman rho coefficient is displayed on each plot. b, Heat map of ATAC-seq peak expression z-score (left) and transcript RNA expression in z-score (right) for 149 TE-chimeric transcripts. c, Dot plot of difference in number of candidates between samples that have a particular driver mutation and those that do not in a specific cancer type. Dots are ordered by difference. Wilcoxon rank sum test (two-sided) was used with Benjamin-Hochberg correction. Supplementary Table 5 has exact p-values. d, Bar plot of the distribution of types of TP53 mutations across cancer types. e, Box and dot plots of global methylation levels of samples with (purple) and without (blue) TP53 mutations. *P < 0.05, **P < 0.01, ***P < 0.001. Wilcoxon rank sum test (two-sided) was used with Benjamin-Hochberg correction. The ‘N=’ lists the number of tumor samples in each boxplot. Expact p-values are the following: LGG: 9.11E-01, SARC: 1.30E-01, LUAD: 5.52E-03, HNSC: 8.03E-02, BRCA: 9.11E-01, COAD: 2.04E-02, STAD: 8.43E-12, LUSC: 1.40E-03, PRAD: 1.75E-03, UCEC: 1.75E-03, BLCA: 6.65E-01, LIHC: 1.75E-03, SKCM: 1.81E-01. f, Box plot of number of tumor samples in each cancer separated by TP53 mutation type. The ‘N=’ lists the number of tumor samples in each boxplot. All box plots follow the following format: center line, median; box limits, upper and lower quartiles; whiskers, 1.5x interquartile range; points, outliers.
Extended Data Fig. 5 Cell line expression of tumor-specific TE-chimeric transcripts.
a, Box plots with overlaid dot plots of the number of candidates expressed in each cancer cell line profiled across various tumor types. The ‘N=’ lists the number of cell lines in each boxplot. Box plot format: center line, median; box limits, upper and lower quartiles; whiskers, 1.5x interquartile range. b, Heatmap of CAGE-seq TPM expression of candidates across the 10 cancer cell lines we profiled. At the top is a dot plot showing how many TCGA tumor samples a candidate is present in.
Extended Data Fig. 6 Open reading frame prediction of tumor-specific TE-chimeric transcripts.
a, Pie charts showing how often the two translation methods (longest reading frame and kozak context) agreed in terms of type of protein product (normal, truncated, chimeric normal, chimeric truncated, and frameshift) and protein sequence. b, Pie charts of number of resulting proteins with Pfam domain loss or transmembrane domain loss. c, Example of multiple Pfam domain loss in the candidate L1HS_COL28A1. d, Example of complete transmembrane domain loss in the candidate L2a_TRPM6. e, Histogram of size distribution of frameshift proteins. f, Histogram of size distribution of prepended amino acids in chimeric proteins. g, Dot plot of the proportion of all tumors in a specific cancer type covered by each candidate. The most shared candidate in each cancer is labeled.
Extended Data Fig. 7 CPTAC confirmation of TS-TEP protein sequences.
a, Dot plot of the number of TS-TEPs predicted to be in each of the BRCA samples available from CPTAC. The colored dots are samples where at least one TS-TEP candidate was validated. b, Same as (a) but for OV. c, Box plot with overlaid dot plot of the RNA expression of detected TS-TEPs across all the BRCA samples profiled. Highlighted dots are the candidate-sample combinations validated by mass spectrometry. d, Same as (c) but for OV. The ‘N=’ lists the number of expression values that are summarized by the box plot. Box plot format: center line, median; box limits, upper and lower quartiles; whiskers, 1.5x interquartile range. e, Diagram of transcript with the open reading frame location (top) and diagram of protein structure (bottom) for LTR33_SPINK4 which was found in the BRCA dataset. f, Same as (e) but for MLT1C_SPARCL1. g, Number of samples candidate is present in for each cancer type for LTR33_SPINK4. h, Same as (g) but for MLT1C_SPARCL1. i, HLA-binding affinity prediction of candidate TS-TEA protein sequences to the HLA alleles of the 35 BRCA samples where a TS-TEP was detected with mass spectrometry.
Extended Data Fig. 8 HLA-pulldown mass spectrometry detection of TS-TEAs and analysis of repetitiveness.
a, Bar plot of number of HLA-bound peptides detected from our mass spectrometry experiments. Each cell line has 4-5 replicates, and then there is a ‘Total’ bar that is the total number of unique peptides detected from all of the replicates. b, Replicates in which each of the TS-TEA peptides was detected in the DMS 53 cell line. c, CAGE expression of TE-chimeric transcripts that the detected peptides can come from. Two of the candidate peptides have sequences common to multiple candidates that are expressed in the DMS 53 cell line. d, Violin plots with superimposed dot plots of the expression in reads per million (RPM) of genomic loci that can be translated into the peptide LPSEMNPVP. The x-axis groups the data by study and then ‘candidate’ loci that come from TE-chimeric transcripts identified in the paper and ‘not candidate’ loci which are other genomic locations that can also make the same peptide. e, Same as (d) but for the peptide SPSSASLTL. f, Same as (d) but for the peptide SPSSASLAL. g, Scatter plot of all TS-TEP candidates where the x-axis is the log2-transformed number of antigenic 9-mers that can be generated from the candidate and the y-axis is the log2-transformed number of genomic loci encoding a 9-mer averaged across all antigenic 9-mers for a TS-TEP. The size of the dot is proportional to the number of tumor samples the TS-TEP is present in, and the color of the dot is the class of transposable element. h, Box plot and violin plot of the log2-transformed number of antigenic 9-mers that can be generated from each TS-TEP candidate (left) and the log2-transformed number of genomic loci encoding a 9-mer averaged across all antigenic 9-mers for each candidate (right) categorized by TE class. The ‘N=’ lists the number of candidates summarized by each box plot. Box plot format: center line, median; box limits, upper and lower quartiles; whiskers, 1.5x interquartile range. i, For the candidate L1P2_STK31, a line graph with the x-axis showing the amino acid and position of amino acids at the N-terminus of the protein, and the y-axis is the number of genomic loci that can translate into the 9-mer. Each dot represents the 9-mer that ends with the amino acid below it on the x-axis. Below the plot is a schematic of the portion of the protein translated from the TE (subfamily is L1P2) and the canonical exons of the gene (STK31).
Extended Data Fig. 9 Repetitive nature of antigens and optimal antigen combination for TCGA.
a, Number of genomic loci HLA-bound TE peptides from another study could originate from using BLAT. b, mTEC and TEC expression of all 2,297 candidates. c, Bar graph of the number of mTEC or TEC samples the candidate is detected in. Only those candidates found in multiple mTEC or TEC samples are shown. d, Bar graph of the number of tumor samples that each candidate is present in for the optimal combination of 20 TS-TEAs that would cover the most TCGA samples (bottom). At the top, a line plot showing the cumulative number of tumor samples covered by that number of candidates.
Extended Data Fig. 10 Synthetic peptide validation of HLA-bound TS-TEAs.
a–d, For each detected TS-TEA peptide, the spectra of the peptide found in our HLA-pulldown experiments is displayed on the top in blue, and the spectra of the synthetic peptide is displayed on the bottom in red. The number of common peaks is listed.
Supplementary information
Supplementary Information
Supplementary Methods and Figs. 1–5.
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Supplementary Tables 1–17.
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Unprocessed western blot without annotation and unprocessed fluorescence microscope image.
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Shah, N.M., Jang, H.J., Liang, Y. et al. Pan-cancer analysis identifies tumor-specific antigens derived from transposable elements. Nat Genet 55, 631–639 (2023). https://doi.org/10.1038/s41588-023-01349-3
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DOI: https://doi.org/10.1038/s41588-023-01349-3
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