Takahashi et al. established a multi-site murine tumor model system for temporal tracking of CD8+ T cell phenotypes and clonal dynamics, identifying a “precursor exhausted” PD-1+Ly108+ population as a driver of clonal expansion. DEG analysis revealed an “expansion signature” that correlated with future expansion in baseline samples from patients treated with ICB. Therapeutic responses and survival were associated with higher expansion scores in post-treatment, but not pre-treatment samples. In the murine model, LAG3 blockade uniquely enhanced the total expansion signature by selectively re-expanding previously contracted existing clones.
Contributed by Morgan Janes
ABSTRACT: Effective cancer immunotherapy relies on the clonal proliferation and expansion of CD8(+) T cells in the tumor. However, our insights into clonal expansions are limited, owing to an inability to track the same clones in tumors over time. Here, we develop a multi-site tumor mouse model system to track hundreds of expanding and contracting CD8(+) T cell clones over multiple timepoints in tumors of the same individual. Through coupling of clonal expansion dynamics and single-cell RNA/TCR-seq data, we identify a transcriptomic signature in PD-1(+)Ly108(+) precursor exhausted cells that strongly predicts rates of intratumoral clone expansion. The signature correlates with expansion in mice, both with and without immunotherapies, and in patients undergoing PD-1 blockade therapy. Expression of the signature during treatment corresponds with positive clinical outcomes. Downregulation of the signature precedes clone contraction-a phase in which clones contract but maintain revivable precursor exhausted cells in the tumor. LAG-3 blockade re-activates the expansion signature, re-expanding pre-existing clones, including previously contracted clones. These findings reveal how the study of clonal expansion dynamics provide a powerful 'pan-immunotherapy' signature for monitoring immunotherapies with implications for their future development.
Author Info: (1) Medical Research Council Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge, CB2 1QR, UK. munetomo.takahashi@gmail.com. Department of Prev
Author Info: (1) Medical Research Council Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge, CB2 1QR, UK. munetomo.takahashi@gmail.com. Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. munetomo.takahashi@gmail.com. (2) Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. (3) Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. Department of Host-Microbe Interactions, St. Jude Children's Research Hospital, Memphis, TN, USA. (4) Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. (5) Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. (6) Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. (7) Department of Immunology and Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, B15 2TT, UK. (8) Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. (9) Medical Research Council Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge, CB2 1QR, UK. (10) Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. (11) Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. ueha@rs.tus.ac.jp.
