A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types

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.

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Publication Details

Journal
Nature Communications
Published
2025-02-03
DOI
https://doi.org/10.1038/s41467-024-55059-3
Citations
11
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
Field-Weighted Citation Impact
11.50

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article

A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types

Saumya Jani, Candice D. Church, Hongkai Ji, J. L. Wilson et al.
11 citations
Nature Communications
Cancer Immunotherapy and Biomarkers
11.50
article

A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types

Saumya Jani, Candice D. Church, Hongkai Ji, J. L. Wilson, Rima M. Kulikauskas, Thomas H. Pulliam, Sydney Connor, Suzanne L. Topalian, Patrick M. Forde, Drew M. Pardoll, Kellie N. Smith, Paul Nghiem, Zhen Zeng, Jiajia Zhang, Shuai Li, Zhao Yi-min, Boyang Zhang, Tianbei Zhang, Dipika Singh
article en
11 citations

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.

Nature CommunicationsVol. 16(1)
Bloomberg (United States) (US), Johns Hopkins University (US), University of California, Los Angeles (US), University of Washington (US), Johns Hopkins Medicine (US), Fred Hutch Cancer Center (US), Sidney Kimmel Cancer Center (US), Advanced Imaging Research (United States) (US)
Cancer Research Institute, LUNGevity Foundation, Bristol-Myers Squibb, Swim Across America, National Institutes of Health, Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Good health and well-being
Openalex Percentile: Top 1%
Cancer Immunotherapy and Biomarkers
11.50
DOIOpen Access PDFOpenAlex
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