Barboy et al. leveraged scRNAseq to track temporal transitions in T cell phenotypes across compartments in multiple mouse tumor models, identifying 7 novel, functional programs that spanned a continuum of T cell states. PD-1 blockade was directly associated with upregulation of early effector and dysfunction programs, and played an independent role in promoting T cell recruitment and proliferation via cDC1s in the tumor and dLN. Combination treatment with anti-PD-1 and a 4-1BB agonist was associated with an influx of activated precursor cells and strong induction of early effector programs, demonstrating the potential of 4-1BB agonism to supplement the role of cDC1s in deficient tumors.
Contributed by Morgan Janes
ABSTRACT: Successful immunotherapy relies on triggering complex responses involving T cell dynamics in tumors and the periphery. Characterizing these responses remains challenging using static human single-cell atlases or mouse models. To address this, we developed a framework for in vivo tracking of tumor-specific CD8(+) T cells over time and at single-cell resolution. Our tools facilitate the modeling of gene program dynamics in the tumor microenvironment (TME) and the tumor-draining lymph node (tdLN). Using this approach, we characterize two modes of anti-programmed cell death protein 1 (PD-1) activity, decoupling induced differentiation of tumor-specific activated precursor cells from conventional type 1 dendritic cell (cDC1)-dependent proliferation and recruitment to the TME. We demonstrate that combining anti-PD-1 therapy with anti-4-1BB agonist enhances the recruitment and proliferation of activated precursors, resulting in tumor control. These data suggest that effective response to anti-PD-1 therapy is dependent on sufficient influx of activated precursor CD8(+) cells to the TME and highlight the importance of understanding system-level dynamics in optimizing immunotherapies.
Author Info: (1) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (2) Department of Computer Science and Applied Mathematics and Department of Molecular Cell Bi
Author Info: (1) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (2) Department of Computer Science and Applied Mathematics and Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (3) Department of Synthetic Immunology, Shenzhen Institutes of Advanced Technology, Shenzhen, China. (4) Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK. (5) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (6) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (7) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. Department of Bioengineering, University of Washington, Seattle, WA, USA. (8) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (9) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (10) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (11) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (12) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (13) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. The Hebrew University, Jerusalem, Israel. (14) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (15) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (16) Department of Clinical Microbiology and Immunology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (17) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (18) Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA. (19) Department of Computer Science and Applied Mathematics and Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (20) Department of Computer Science and Applied Mathematics and Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. amos.tanay@weizmann.ac.il. (21) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. ido.amit@weizmann.ac.il.
