B Cell-Like Neutrophil Found in Peripheral Blood of Melanoma Patients Melissa A. Meyer1*, Huy Q. Dinh1,2*, Yanfang Zhu1,3, Shu Liang1, Gregory Seumois1, Pandurangan Vijayanand1, Sergio Catz4, Christian Ottensmeier5, and Catherine C. Hedrick1 1Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA, USA, 2McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA, 3Department of Pediatrics, University of California San Diego, La Jolla, CA, USA, 4Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA, 5University of Southampton, Southampton, UK. *Equal contributions Neutrophils engage both pro- and anti-tumoral functions. We hypothesized that the heterogeneity observed amongst neutrophils in the periphery during cancer is seeded by heterogeneity amongst immature neutrophils populations in the bone marrow (BM). To test this, we employed single-cell transcriptomics to profile immature neutrophils from the healthy human BM. We identified a novel neutrophil subset that expresses several B cell markers, including CD79A/B, components of the B cell receptor and PAX5, a B cell-specific transcription factor. We termed this population BNeuts. BNeuts are more like neutrophils than B cells, with a neutrophil-like transcriptome, a large, granular cytoplasm, and a superior ability to engage NETosis. Using lineage-tracing studies, we determined that BNeuts derive from early human neutrophil progenitors rather than human B cell progenitors. We found that BNeuts are confined to the BM of healthy individuals but expand into the blood of melanoma patients, specifically in early-stage disease. BNeuts are also found in the tumors of head and neck cancer patients, showing they can infiltrate tumor tissue. To understand why neutrophils might employ a B cell program, we tested classical B cell functions within this cell type. We found BNeuts engaged an antigen presentation program, a function that is usually absent in neutrophils. We show that BNeuts phagocytize tumor cells, have increased expression of antigen presentation-related genes compared to other neutrophils, and modulate CD4+ T cell responses. Together, we have identified a novel neutrophil subset expressing B cell markers that is preferentially expanded in the blood of melanoma patients and poised to control T cell responses in cancer.