Functionally heterogeneous intratumoral CD4 <sup>+</sup> CD8 <sup>+</sup> double-positive T cells can give rise to single-positive T cells
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Tony Li
Department of Materials Science and Engineering, Stanford University
Arielle Ilano
Division of Hematology/Oncology, Department of Medicine, University of California
Marcel Arias-Badia
Division of Hematology/Oncology, Department of Medicine, University of California
Diamond Luong
Division of Hematology/Oncology, Department of Medicine, University of California
Hewitt Chang
Division of Hematology/Oncology, Department of Medicine, University of California
Serena S. Kwek
Division of Hematology/Oncology, Department of Medicine, University of California
Kathryn Allaire
Division of Hematology/Oncology, Department of Medicine, University of California
Arun Chumber
Division of Hematology/Oncology, Department of Medicine, University of California
Mason Sakamoto
Division of Hematology/Oncology, Department of Medicine, University of California
Matthew Clark
Division of Hematology/Oncology, Department of Medicine, University of California
Averey Lea
Division of Hematology/Oncology, Department of Medicine, University of California
Mark Bridge
Helen Diller Family Comprehensive Cancer Center, University of California
Brandon Chen
Eric Liu
Division of Hematology/Oncology, Department of Medicine, University of California
Sima Porten
Division of Hematology/Oncology, Department of Medicine University of California‐San Francisco San Francisco California USA
Maxwell V. Meng
Department of Urology, University of California
Lauren I. R. Ehrlich
Department of Molecular Biosciences, The University of Texas at Austin
David Y. Oh
Division of Hematology/Oncology, Department of Medicine, University of California
Lawrence Fong
Division of Hematology/Oncology, Department of Medicine, University of California