Fc\u03b3R engagement reprograms neutrophils into antigen cross-presenting cells that elicit acquired anti-tumor immunity

Vijayashree Mysore,Andrew H Lichtman,Pei X Liew,Koshu Okubo,Florencia Rosetti,Soumya Raychaudhuri,Xavier Cullere,Iris Madera-Salcedo,Ulrich H Von Andrian,Frank Rosenbauer,Richard M Stone,Fan Zhang,Tanya N Mayadas,Jon C Aster,Joseph Mears

doi:10.1038/s41467-021-24591-x

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.

Highlights

Classical dendritic cells are professional antigen-presenting cells (APC) that regulate immunity and tolerance
We found that CD45.1+ Ova-immune complexes (ICs)-pretreated neutrophils were unable to upregulate neutrophil-derived APCs (nAPC) markers in CD45.2+ Ova or anti-Ova pretreated neutrophils (Fig. 1c)
Our work shows that binding of ICs or a human FcγRIIIB antibody–antigen conjugate rapidly converts mature neutrophils to nAPCs in a process that requires Fcγ receptors (FcγRs) endocytosis

Summary

Introduction

Classical dendritic cells (cDC) are professional antigen-presenting cells (APC) that regulate immunity and tolerance. 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 antitumor immunity in mice. Our data demonstrate that neutrophil endocytosis of antibody–antigen complexes via FcγRs or FcγRIIIB engagement with an anti-FcγRIIIB-antigen conjugate rapidly converts them into fully immunogenic nAPCs, and the number of nAPCs in lupus patient blood correlates with disease outcomes. We define the transcriptome of nAPCs and the transcriptional program driving neutrophil to APC conversion downstream of GM-CSF and/or FcγRs. Of therapeutic relevance, we show that nAPCs induce anti-tumor immunity in mice and when generated from human neutrophils can reactivate autologous antigen-specific memory T cells in vitro. Neutrophil FcγRs provide a direct link between innate and adaptive immunity and may be targeted as a strategy to generate a large number of immunogenic nAPCs for T cellbased immunotherapy

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Results

Conclusion