Fc?R engagement reprograms neutrophils into antigen cross-presenting cells that elicit acquired anti-tumor immunity

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 after culture of neutrophils with cytokines and in human diseases. Here, we show that FcgR-mediated endocytosis of antigen-antibody complexes or an anti-FcgRIIIB-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. Single cell transcript analyses and validation studies implicate the transcription factor PU.1 in neutrophil to nAPC conversion. In humans, nAPC frequency in lupus patient blood containing IgG-immune complexes correlates with disease. Moreover, conjugate treatment of neutrophils from individuals with myeloid neoplasms that harbor neoantigens or those who are vaccinated against bacterial toxins generates nAPCs that activate autologous T cells. Thus, anti-FcgRIIIB-antigen conjugate-induced conversion of neutrophils to immunogenic nAPCs may represent a new immunotherapy for cancer and infectious diseases. Overall design: i) Sorted splenic Ly6G+CD11c+/-MHCII+/- cells isolated from three Fc?R humanized mice after treatment with 3G8-conjugate, ii) neutrophils cultured in vitro with 3G8-conjugate and collected at day 0, 1, 2, and 3, and iii) splenic cells from untreated wild-type mice and Fc?R humanized mice.