Functionally heterogeneous intratumoral CD4+CD8+double-positive T cells can give rise to single-positive T cells

• 成果类型: Article
• 署名作者: Li, Tony; Ilano, Arielle; Arias-Badia, Marcel; Luong, Diamond; Chang, Hewitt; Kwek, Serena S.; Allaire, Kathryn; Chumber, Arun; Sakamoto, Mason; Clark, Matthew; Lea, Averey; Bridge, Mark; Chen, Brandon; Liu, Eric; Porten, Sima; Meng, Maxwell, V; Erlich, Lauren I. R.; Oh, David Y.; Fong, Lawrence
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; University of California System; University of California San Francisco; University of Texas System; University of Texas Austin; University of California System; University of California San Francisco; Fred Hutchinson Cancer Center
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2506168123
• 发表日期: 2026-01-27
• 页码: e2506168123
• 关键词: immunotherapy; tumor immunity; T cells; lymphocytes; expression; cd4(+); gene

摘要

Conventional single-positive (SP) CD4+ and CD8+ T cells recognize tumor antigens and help mediate clinical responses with cancer immunotherapy. Double-positive CD4+CD8+ (DP) T cells have also been described in human cancers, but their role in the tumor microenvironment remains unclear. By generating a multiomic single cell atlas of DP and SP T cells, we find that DP T cells possess phenotypic heterogeneity similar to SP T cells that includes multiple clonally expanded populations of cytotoxic DP T cells in human renal cell carcinoma (RCC). These intratumoral DP T cells can mediate both MHC class I-and class II-dependent killing of autologous tumor cells. In addition, transcriptional profiling of DP TCR-bearing T cells revealed a gene signature enriched for clinical responders to PD-1 blockade in advanced RCC. We confirm prior observations of SP T cells transitioning into DP T cells and more notably, demonstrate that intratumoral T cells are capable of bidirectional differentiation in which DP T cells serve as precursors to SP T cell sin vivo. In the latter scenario, intratumoral DP T cells are shown to express Rag2, suggesting that the tumor may act as an extrathymic site of T cell development. These findings reveal the multiple roles that DP T cells can possess in antitumor immunity.