Targeting of the CD161 inhibitory receptor enhances T-cell-mediated immunity against hematological malignancies.

Autor:	Alvarez Calderon F; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA.; Harvard Medical School, Boston, MA., Kang BH; Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Cambridge, MA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA., Kyrysyuk O; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Zheng S; Department of Genetics and Genomic Sciences, Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY., Wang H; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.; Department of Immunology, Harvard Medical School, Boston, MA., Mathewson ND; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.; Department of Immunology, Harvard Medical School, Boston, MA.; Department of Neurology, Brigham and Women's Hospital, Boston, MA., Luoma AM; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.; Department of Immunology, Harvard Medical School, Boston, MA., Ning X; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.; Department of Immunology, Harvard Medical School, Boston, MA., Pyrdol J; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Cao X; Department of Genetics and Genomic Sciences, Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY., Suvà ML; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA., Yuan GC; Department of Genetics and Genomic Sciences, Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY., Wittrup KD; Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Cambridge, MA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA.; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA., Wucherpfennig KW; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.; Harvard Medical School, Boston, MA.; Department of Immunology, Harvard Medical School, Boston, MA.; Department of Neurology, Brigham and Women's Hospital, Boston, MA.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2024 Mar 21; Vol. 143 (12), pp. 1124-1138.
DOI:	10.1182/blood.2023022882
Abstrakt:	Abstract: The CD161 inhibitory receptor is highly upregulated by tumor-infiltrating T cells in multiple human solid tumor types, and its ligand, CLEC2D, is expressed by both tumor cells and infiltrating myeloid cells. Here, we assessed the role of the CD161 receptor in hematological malignancies. Systematic analysis of CLEC2D expression using the Cancer Cell Line Encyclopedia revealed that CLEC2D messenger RNA was most abundant in hematological malignancies, including B-cell and T-cell lymphomas as well as lymphocytic and myelogenous leukemias. CLEC2D protein was detected by flow cytometry on a panel of cell lines representing a diverse set of hematological malignancies. We, therefore, used yeast display to generate a panel of high-affinity, fully human CD161 monoclonal antibodies (mAbs) that blocked CLEC2D binding. These mAbs were specific for CD161 and had a similar affinity for human and nonhuman primate CD161, a property relevant for clinical translation. A high-affinity CD161 mAb enhanced key aspects of T-cell function, including cytotoxicity, cytokine production, and proliferation, against B-cell lines originating from patients with acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and Burkitt lymphoma. In humanized mouse models, this CD161 mAb enhanced T-cell-mediated immunity, resulting in a significant survival benefit. Single cell RNA-seq data demonstrated that CD161 mAb treatment enhanced expression of cytotoxicity genes by CD4 T cells as well as a tissue-residency program by CD4 and CD8 T cells that is associated with favorable survival outcomes in multiple human cancer types. These fully human mAbs, thus, represent potential immunotherapy agents for hematological malignancies. (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
Databáze:	MEDLINE
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