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

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 and Kellie N. Smith ()
Additional contact information
Zhen Zeng: Bloomberg~Kimmel Institute for Cancer Immunotherapy
Tianbei Zhang: Bloomberg~Kimmel Institute for Cancer Immunotherapy
Jiajia Zhang: University of California
Shuai Li: Johns Hopkins Bloomberg School of Public Health
Sydney Connor: Bloomberg~Kimmel Institute for Cancer Immunotherapy
Boyang Zhang: Johns Hopkins Bloomberg School of Public Health
Yimin Zhao: Johns Hopkins Bloomberg School of Public Health
Jordan Wilson: Johns Hopkins Bloomberg School of Public Health
Dipika Singh: Bloomberg~Kimmel Institute for Cancer Immunotherapy
Rima Kulikauskas: Fred Hutchinson Cancer Center
Candice D. Church: Fred Hutchinson Cancer Center
Thomas H. Pulliam: Fred Hutchinson Cancer Center
Saumya Jani: Fred Hutchinson Cancer Center
Paul Nghiem: Fred Hutchinson Cancer Center
Suzanne L. Topalian: Bloomberg~Kimmel Institute for Cancer Immunotherapy
Patrick M. Forde: Bloomberg~Kimmel Institute for Cancer Immunotherapy
Drew M. Pardoll: Bloomberg~Kimmel Institute for Cancer Immunotherapy
Hongkai Ji: Johns Hopkins Bloomberg School of Public Health
Kellie N. Smith: Bloomberg~Kimmel Institute for Cancer Immunotherapy

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-55059-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55059-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-55059-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().