A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types
Abstract Identifying tumor-specific T cell clones that mediate immunotherapy responses remains challenging. Mutation-associated neoantigen (MANA) -specific CD8+ tumor-infiltrating lymphocytes (TIL) have been shown to express high levels of CXCL13 and CD39 (ENTPD1), and low IL-7 receptor (IL7R) level...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55059-3 |
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| author | Zhen Zeng Tianbei Zhang Jiajia Zhang Shuai Li Sydney Connor Boyang Zhang Yimin Zhao Jordan Wilson Dipika Singh Rima Kulikauskas Candice D. Church Thomas H. Pulliam Saumya Jani Paul Nghiem Suzanne L. Topalian Patrick M. Forde Drew M. Pardoll Hongkai Ji Kellie N. Smith |
| author_facet | Zhen Zeng Tianbei Zhang Jiajia Zhang Shuai Li Sydney Connor Boyang Zhang Yimin Zhao Jordan Wilson Dipika Singh Rima Kulikauskas Candice D. Church Thomas H. Pulliam Saumya Jani Paul Nghiem Suzanne L. Topalian Patrick M. Forde Drew M. Pardoll Hongkai Ji Kellie N. Smith |
| author_sort | Zhen Zeng |
| collection | DOAJ |
| description | Abstract Identifying tumor-specific T cell clones that mediate immunotherapy responses remains challenging. Mutation-associated neoantigen (MANA) -specific CD8+ tumor-infiltrating lymphocytes (TIL) have been shown to express high levels of CXCL13 and CD39 (ENTPD1), and low IL-7 receptor (IL7R) levels in many cancer types, but their collective relevance to T cell functionality has not been established. Here we present an integrative tool to identify MANA-specific TIL using weighted expression levels of these three genes in lung cancer and melanoma single-cell RNAseq datasets. Our three-gene “MANAscore” algorithm outperforms other RNAseq-based algorithms in identifying validated neoantigen-specific CD8+ clones, and accurately identifies TILs that recognize other classes of tumor antigens, including cancer testis antigens, endogenous retroviruses and viral oncogenes. Most of these TIL are characterized by a tissue resident memory gene expression program. Putative tumor-reactive cells (pTRC) identified via MANAscore in anti-PD-1-treated lung tumors had higher expression of checkpoint and cytotoxicity-related genes relative to putative non-tumor-reactive cells. pTRC in pathologically responding tumors showed distinguished gene expression patterns and trajectories. Collectively, we show that MANAscore is a robust tool that can greatly enrich candidate tumor-specific T cells and be used to understand the functional programming of tumor-reactive TIL. |
| format | Article |
| id | doaj-art-2a5aadf21d3f462f96ca726c4063a1dc |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-2a5aadf21d3f462f96ca726c4063a1dc2025-02-09T12:46:12ZengNature PortfolioNature Communications2041-17232025-02-0116111710.1038/s41467-024-55059-3A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer typesZhen Zeng0Tianbei Zhang1Jiajia Zhang2Shuai Li3Sydney Connor4Boyang Zhang5Yimin Zhao6Jordan Wilson7Dipika Singh8Rima Kulikauskas9Candice D. Church10Thomas H. Pulliam11Saumya Jani12Paul Nghiem13Suzanne L. Topalian14Patrick M. Forde15Drew M. Pardoll16Hongkai Ji17Kellie N. Smith18Bloomberg~Kimmel Institute for Cancer ImmunotherapyBloomberg~Kimmel Institute for Cancer ImmunotherapyDavid Geffen School of Medicine, University of CaliforniaDepartment of Biostatistics, Johns Hopkins Bloomberg School of Public HealthBloomberg~Kimmel Institute for Cancer ImmunotherapyDepartment of Biostatistics, Johns Hopkins Bloomberg School of Public HealthDepartment of Biostatistics, Johns Hopkins Bloomberg School of Public HealthDepartment of Biostatistics, Johns Hopkins Bloomberg School of Public HealthBloomberg~Kimmel Institute for Cancer ImmunotherapyFred Hutchinson Cancer CenterFred Hutchinson Cancer CenterFred Hutchinson Cancer CenterFred Hutchinson Cancer CenterFred Hutchinson Cancer CenterBloomberg~Kimmel Institute for Cancer ImmunotherapyBloomberg~Kimmel Institute for Cancer ImmunotherapyBloomberg~Kimmel Institute for Cancer ImmunotherapyDepartment of Biostatistics, Johns Hopkins Bloomberg School of Public HealthBloomberg~Kimmel Institute for Cancer ImmunotherapyAbstract Identifying tumor-specific T cell clones that mediate immunotherapy responses remains challenging. Mutation-associated neoantigen (MANA) -specific CD8+ tumor-infiltrating lymphocytes (TIL) have been shown to express high levels of CXCL13 and CD39 (ENTPD1), and low IL-7 receptor (IL7R) levels in many cancer types, but their collective relevance to T cell functionality has not been established. Here we present an integrative tool to identify MANA-specific TIL using weighted expression levels of these three genes in lung cancer and melanoma single-cell RNAseq datasets. Our three-gene “MANAscore” algorithm outperforms other RNAseq-based algorithms in identifying validated neoantigen-specific CD8+ clones, and accurately identifies TILs that recognize other classes of tumor antigens, including cancer testis antigens, endogenous retroviruses and viral oncogenes. Most of these TIL are characterized by a tissue resident memory gene expression program. Putative tumor-reactive cells (pTRC) identified via MANAscore in anti-PD-1-treated lung tumors had higher expression of checkpoint and cytotoxicity-related genes relative to putative non-tumor-reactive cells. pTRC in pathologically responding tumors showed distinguished gene expression patterns and trajectories. Collectively, we show that MANAscore is a robust tool that can greatly enrich candidate tumor-specific T cells and be used to understand the functional programming of tumor-reactive TIL.https://doi.org/10.1038/s41467-024-55059-3 |
| spellingShingle | Zhen Zeng Tianbei Zhang Jiajia Zhang Shuai Li Sydney Connor Boyang Zhang Yimin Zhao Jordan Wilson Dipika Singh Rima Kulikauskas Candice D. Church Thomas H. Pulliam Saumya Jani Paul Nghiem Suzanne L. Topalian Patrick M. Forde Drew M. Pardoll Hongkai Ji Kellie N. Smith A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types Nature Communications |
| title | A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types |
| title_full | A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types |
| title_fullStr | A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types |
| title_full_unstemmed | A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types |
| title_short | A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types |
| title_sort | minimal gene set characterizes til specific for diverse tumor antigens across different cancer types |
| url | https://doi.org/10.1038/s41467-024-55059-3 |
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