PD-1 combination therapy with IL-2 modifies CD8 + T cell exhaustion program.

Autor: Hashimoto M; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA., Araki K; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.; Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA., Cardenas MA; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Li P; Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA., Jadhav RR; Department of Immunology, Mayo Clinic School of Medicine and Sciences, Rochester, MN, USA.; Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA., Kissick HT; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.; Department of Urology, Emory University School of Medicine, Atlanta, GA, USA.; Winship Cancer Institute, Emory University, Atlanta, GA, USA., Hudson WH; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA., McGuire DJ; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA., Obeng RC; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.; Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.; Department of Pathology and Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Wieland A; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.; Department of Otolaryngology, The Ohio State University College of Medicine, Columbus, OH, USA.; The Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Lee J; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA., McManus DT; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA., Ross JL; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA., Im SJ; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.; Department of Immunology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea., Lee J; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.; Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea., Lin JX; Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA., Hu B; Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA., West EE; Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA.; Complement and Inflammation Research Section (CIRS), National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA., Scharer CD; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA., Freeman GJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Sharpe AH; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA., Ramalingam SS; Winship Cancer Institute, Emory University, Atlanta, GA, USA.; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA., Pellerin A; Biogen, Cambridge, MA, USA., Teichgräber V; Roche Innovation Center Basel, Basel, Switzerland., Greenleaf WJ; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Klein C; Roche Innovation Center Zurich, Schlieren, Switzerland., Goronzy JJ; Department of Immunology, Mayo Clinic School of Medicine and Sciences, Rochester, MN, USA.; Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA., Umaña P; Roche Innovation Center Zurich, Schlieren, Switzerland., Leonard WJ; Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA., Smith KA; Department of Medicine, Division of Immunology, Weill Medical College of Cornell University, New York, NY, USA., Ahmed R; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. rahmed@emory.edu.; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. rahmed@emory.edu.; Winship Cancer Institute, Emory University, Atlanta, GA, USA. rahmed@emory.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2022 Oct; Vol. 610 (7930), pp. 173-181. Date of Electronic Publication: 2022 Sep 28.
DOI: 10.1038/s41586-022-05257-0
Abstrakt: Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection 1 . Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1 + TCF1 + stem-like CD8 +  T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8 +  T cells that resemble highly functional effector CD8 +  T cells seen after an acute viral infection. The generation of these qualitatively superior CD8 + T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1 + TCF1 + stem-like CD8 + T cells, also referred to as precursors of exhausted CD8 + T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8 + T cells emerging from the stem-like CD8 + T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25-CD122-CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1 + IL-2 combination therapy. There is considerable interest in PD-1 + IL-2 combination therapy for patients with cancer 2,3 , and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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