slanþ Monocytes Kill Cancer Cells Coated in Therapeutic Antibody by Trogoptosis

Abstract

Monocytes positive for 6-Sulfo LacNAc (slan) are a major subset of nonclassical CD14dimCD16þ monocytes in humans. We have shown that slanþ cells infiltrate lymphomas and elicit an antibody-dependent cellular cytotoxicity (ADCC) of neoplastic B cells mediated by the anti-CD20 therapeutic rituximab. Herein, by performing blocking experiments and flow cytometry analyses, as well as confocal microscopy and live-cell imaging assays, we extended the findings to other humanized antibodies and deciphered the underlying effector mechanism(s). Specifically, we show that, after coculture with target cells coated with anti-CD20 or anti-CD38, slanþ monocytes mediate trogocytosis, a cell–cell contact dependent, antibody-mediated process that triggers an active, mechanic disruption of target cell membranes. Trogocytosis by slanþ monocytes leads to a necrotic type of target cell death known as trogoptosis, which, once initiated, was partially sustained by endogenous TNFa. We also found that slanþ monocytes, unlike natural killer (NK) cells, mediate a direct ADCC with all types of anti-CD47 analyzed, and this was independent of their IgG isotype. The latter findings unveil a potentially relevant contribution by slanþ monocytes in mediating the therapeutic efficacy of antiCD47 in clinical practice, which could be particularly important when NK cells are exhausted or deficient in number. Overall, our observations shed new light on the cytotoxic mechanisms exerted by slanþ monocytes in antibody-dependent tumor cell targeting and advance our knowledge on how to expand our therapeutic arsenal for cancer therapy.