Bibliographic Details
| Title: |
A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types. |
| Authors: |
Zeng, Zhen, Zhang, Tianbei, Zhang, Jiajia, Li, Shuai, Connor, Sydney, Zhang, Boyang, Zhao, Yimin, Wilson, Jordan, Singh, Dipika, Kulikauskas, Rima, Church, Candice D., Pulliam, Thomas H., Jani, Saumya, Nghiem, Paul, Topalian, Suzanne L., Forde, Patrick M., Pardoll, Drew M., Ji, Hongkai, Smith, Kellie N. |
| Source: |
Nature Communications; 2/3/2025, Vol. 16 Issue 1, p1-17, 17p |
| Subject Terms: |
TUMOR antigens, MEDICAL sciences, GENE expression, T cells, FUNCTIONAL programming (Computer science), LUNGS |
| 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. Although individual genes that distinguish tumor-reactive CD8+ T cells from bystander T cells in tumors have been described, a functionally meaningful integrative signature has not been established. Here authors show that mutation-associated neoantigen-specific CD8+ tumor-infiltrating lymphocytes can be recognized by MANAscore, an algorithm that uses weighted expression levels of CXCL13, ENTPD1 and IL7R in single-cell RNAseq datasets of lung cancer and melanoma patients as input. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
