Wang et al. performed paired single-cell RNA and T cell receptor sequencing in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy to study the pharmacodynamic responses of CD8+ T cells to checkpoint blockade. Clonotypic trajectory analyses using a novel algorithm, Cyclone, showed waves of clonal responses with distinct temporal kinetics and cellular compositions. Combination therapy reinvigorated progenitor and differentiated exhausted CD8+ T cells, with anti-CTLA-4 resulting in expansion of progenitor exhausted CD8+ T cells, and anti-PD-1 driving their differentiation.
Contributed by Shishir Pant
ABSTRACT: Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy. We develop the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induces waves of clonal T cell responses that peak at distinct time points. Combination therapy results in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8(+) T cells and exhausted CD8(+) T cell (T(EX)) clones. Focused analyses of T(EX) identify that anti-CTLA-4 induces robust expansion and proliferation of progenitor T(EX), which synergizes with anti-PD-1 to reinvigorate T(EX) during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.
Author Info: (1) Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Division of Hematology/Oncolo
Author Info: (1) Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (3) Immunai Inc, New York, NY 10016, USA. (4) Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (5) Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (6) Department of Medicine, Grossman School of Medicine, New York University, New York, NY 10016, USA. (7) Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (8) Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (9) Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (10) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (11) Immunai Inc, New York, NY 10016, USA. (12) Immunai Inc, New York, NY 10016, USA. (13) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (14) Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (15) Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (16) Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (17) Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (18) Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (19) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (20) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (21) Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (22) Institut Curie, PSL University, Inserm U932, Immunity and Cancer, 75005 Paris, France; Clinical Immunology and Immunomonitoring Laboratory, Institut Curie, Paris, France. (23) Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Tara Miller Melanoma Center, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. (24) Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (25) Bristol Myers Squibb, Princeton, NJ 08540, USA. (26) Tara Miller Melanoma Center, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (27) Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Tara Miller Melanoma Center, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (28) Tara Miller Melanoma Center, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (29) Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Tara Miller Melanoma Center, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (30) Institute for Immunology and Immune Health, Philadelphia, PA 19104, USA. (31) Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (32) Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology and Immune Health, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Philadelphia, PA 19104, USA. (33) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Department of Medical Oncology, Leiden University Medical Center (LUMC), Leiden 2333 ZA, the Netherlands; Department of Hematology and Oncology, University Clinic of Regensburg (UKR), 93053 Regensburg, Germany. (34) Department of Medicine, Grossman School of Medicine, New York University, New York, NY 10016, USA. (35) Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Tara Miller Melanoma Center, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (36) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (37) Department of Medicine, Grossman School of Medicine, New York University, New York, NY 10016, USA. Electronic address: ramin.herati@nyulangone.org. (38) Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Tara Miller Melanoma Center, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology and Immune Health, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Philadelphia, PA 19104, USA; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: alexander.huang@pennmedicine.upenn.edu.
