Van der Sluis, Beyrend et al. studied the dynamic changes in the phenotypes and transcriptomes of T cells following individual or combined treatment with PD-L1 blockade and OX40 agonism in murine tumor models, and identified CD8+ T cells with enhanced cytotoxic and migratory properties. These therapy-responsive T cells expressed high levels of granzyme B and NK receptors (O-glycosylated CD43 [CD431B11], NKG2A, NKG2D, and KLRG1). Blockade or KO of CD43, NKG2D and CXCR3 (found on CD431B11 cells) reduced the impact of combined therapy, demonstrating functional relevance. Similar NK markers were found on cytotoxic CD8+ T cells in the blood of patients responsive to anti-PD-1 therapy.
Contributed by Ed Fritsch
ABSTRACT: Immune checkpoint therapy (ICT) has the power to eradicate cancer, but the mechanisms that determine effective therapy-induced immune responses are not fully understood. Here, using high-dimensional single-cell profiling, we interrogate whether the landscape of T cell states in the peripheral blood predict responses to combinatorial targeting of the OX40 costimulatory and PD-1 inhibitory pathways. Single-cell RNA sequencing and mass cytometry expose systemic and dynamic activation states of therapy-responsive CD4(+) and CD8(+) T cells in tumor-bearing mice with expression of distinct natural killer (NK) cell receptors, granzymes, and chemokines/chemokine receptors. Moreover, similar NK cell receptor-expressing CD8(+) T cells are also detected in the blood of immunotherapy-responsive cancer patients. Targeting the NK cell and chemokine receptors in tumor-bearing mice shows the functional importance of these receptors for therapy-induced anti-tumor immunity. These findings provide a better understanding of ICT and highlight the use and targeting of dynamic biomarkers on T cells to improve cancer immunotherapy.
Author Info: (1) Department of Immunology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands. (2) Department of Immunology, Leiden University Medical Center, 2333ZA Leiden, the N
Author Info: (1) Department of Immunology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands. (2) Department of Immunology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands. (3) Department of Immunology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands. (4) Department of Radiology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands; Systems and Biomedical Engineering Department, Faculty of Engineering, Cairo University, Giza 12613, Egypt; Pattern Recognition and Bioinformatics, Delft University of Technology, 2628XE Delft, the Netherlands. (5) Department of Parasitology, Leiden University Center for Infectious Diseases, Leiden University Medical Center, 2333ZA Leiden, the Netherlands. (6) Department of Pulmonary Diseases, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands. (7) Department of Immunology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands. (8) Department of Immunology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands. (9) Department of Immunology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands. (10) Department of Immunology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands. (11) Department of Immunology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands. (12) Department of Immunology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands. (13) Department of Immunology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands. (14) Department of Immunology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands. (15) Central Animal and Transgenic Facility, Leiden University Medical Center, 2333ZA Leiden, the Netherlands. (16) Central Animal and Transgenic Facility, Leiden University Medical Center, 2333ZA Leiden, the Netherlands. (17) Department of Pathology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands. (18) Department of Biomedical Data Sciences, Sequencing Analysis Support Core, Leiden University Medical Center, 2333ZA Leiden, the Netherlands. (19) Department of Internal Medicine, Amsterdam University Medical Center, 1105AZ Amsterdam, the Netherlands. (20) Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands. (21) Department of Pulmonary Diseases, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands. (22) Department of Immunology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands. (23) Department of Immunology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands. Electronic address: r.arens@lumc.nl.
