Single-cell transcriptomics identifies multiple pathways underlying antitumor function of TCR- and CD8αβ-engineered human CD4 + T cells

• Published in: Science advances Vol. 6; no. 27; p. eaaz7809
• Main Authors: Rath, Jan A., Bajwa, Gagan, Carreres, Benoit, Hoyer, Elisabeth, Gruber, Isabelle, Martínez-Paniagua, Melisa A., Yu, Yi-Ru, Nouraee, Nazila, Sadeghi, Fatemeh, Wu, Mengfen, Wang, Tao, Hebeisen, Michael, Rufer, Nathalie, Varadarajan, Navin, Ho, Ping-Chih, Brenner, Malcolm K., Gfeller, David, Arber, Caroline
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 01.07.2020
• Subjects: Animals; CD4-Positive T-Lymphocytes; CD8 Antigens; CD8-Positive T-Lymphocytes; Humans; Immunology; Mice; Neoplasms - metabolism; Receptors, Antigen, T-Cell - metabolism; SciAdv r-articles; Transcriptome
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.aaz7809

TCR-CD8–engineered CD4 + T cells have potent antitumor activity with sustained expression of diverse transcriptional programs. Transgenic coexpression of a class I–restricted tumor antigen–specific T cell receptor (TCR) and CD8αβ (TCR8) redirects antigen specificity of CD4 + T cells. Reinforcement of biophysical properties and early TCR signaling explain how redirected CD4 + T cells recognize target cells, but the transcriptional basis for their acquired antitumor function remains elusive. We, therefore, interrogated redirected human CD4 + and CD8 + T cells by single-cell RNA sequencing and characterized them experimentally in bulk and single-cell assays and a mouse xenograft model. TCR8 expression enhanced CD8 + T cell function and preserved less differentiated CD4 + and CD8 + T cells after tumor challenge. TCR8 + CD4 + T cells were most potent by activating multiple transcriptional programs associated with enhanced antitumor function. We found sustained activation of cytotoxicity, costimulation, oxidative phosphorylation– and proliferation-related genes, and simultaneously reduced differentiation and exhaustion. Our study identifies molecular features of TCR8 expression that can guide the development of enhanced immunotherapies.