FcγR engagement reprograms neutrophils into antigen cross-presenting cells that elicit acquired anti-tumor immunity

(1) Mysore V (2) Cullere X (3) Mears J (4) Rosetti F (5) Okubo K (6) Liew PX (7) Zhang F (8) Madera-Salcedo I (9) Rosenbauer F (10) Stone RM (11) Aster JC (12) von Andrian UH (13) Lichtman AH (14) Raychaudhuri S (15) Mayadas TN

Nature communications - Open Access

To overcome limitations of classical dendritic cell (cDC) immunotherapy, Mysore et al. generated neutrophil-derived APCs (nAPC) with DC properties. Neutrophil to nAPC conversion required FcγR-mediated endocytosis of Ag:Ab complexes or an anti-FcγRIIIB-Ag conjugate, resulting in comparable T cell activation to cDCs, migration to draining lymph nodes, and CD8⁺ T cell-dependent antitumor immunity in mice. Autologous T cell activation occurred with nAPCs generated from malignant neoantigen-expressing neutrophils obtained from myeloid tumors, suggesting translational potential. In lupus patients, blood nAPCs correlated with disease activity.

Contributed by Katherine Turner

ABSTRACT: Classical dendritic cells (cDC) are professional antigen-presenting cells (APC) that regulate immunity and tolerance. Neutrophil-derived cells with properties of DCs (nAPC) are observed in human diseases and after culture of neutrophils with cytokines. Here we show that FcγR-mediated endocytosis of antibody-antigen complexes or an anti-FcγRIIIB-antigen conjugate converts neutrophils into nAPCs that, in contrast to those generated with cytokines alone, activate T cells to levels observed with cDCs and elicit CD8+ T cell-dependent anti-tumor immunity in mice. Single cell transcript analyses and validation studies implicate the transcription factor PU.1 in neutrophil to nAPC conversion. In humans, blood nAPC frequency in lupus patients correlates with disease. Moreover, anti-FcγRIIIB-antigen conjugate treatment induces nAPCs that can activate autologous T cells when using neutrophils from individuals with myeloid neoplasms that harbor neoantigens or those vaccinated against bacterial toxins. Thus, anti-FcγRIIIB-antigen conjugate-induced conversion of neutrophils to immunogenic nAPCs may represent a possible immunotherapy for cancer and infectious diseases.

Author Info: (1) Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (2) Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (3) Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA. Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Division of Rheumatology, Immunology, Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (4) Departamento de Inmunologa y Reumatologa, Instituto Nacional de Ciencias Mdicas y Nutricin Salvador Zubirn, Mexico City, Mexico. (5) Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (6) Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (7) Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA. Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Division of Rheumatology, Immunology, Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (8) Departamento de Inmunologa y Reumatologa, Instituto Nacional de Ciencias Mdicas y Nutricin Salvador Zubirn, Mexico City, Mexico. (9) Institute of Molecular Tumor Biology, University of Muenster, Muenster, Germany. (10) Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. (11) Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (12) Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA. (13) Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (14) Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA. Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Division of Rheumatology, Immunology, Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK. (15) Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. tmayadas@rics.bwh.harvard.edu.

Citation: Nat Commun 2021 Aug 9 12:4791 Epub08/09/2021

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/34373452

FcγR engagement reprograms neutrophils into antigen cross-presenting cells that elicit acquired anti-tumor immunity

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