Vitamin D–dependent induction of cathelicidin in human macrophages results in … – Science Magazine

Abstract

Infiltration by macrophages represents a characteristic morphological hallmark in high-grade lymphatic malignancies such as
Burkitt’s lymphoma (BL). Although macrophages can, in principle, target neoplastic cells and mediate antibody-dependent cellular
cytotoxicity (ADCC), tumor-associated macrophages (TAMs) regularly fail to exert direct cytotoxic functions. The underlying
mechanisms responsible for this observation remain unclear. We demonstrate that inflammatory M1 macrophages kill proliferating
high-grade B cell lymphoma cells by releasing the antimicrobial peptide cathelicidin in a vitamin D–dependent fashion. We
show that cathelicidin directly induces cell death by targeting mitochondria of BL cells. In contrast, anti-inflammatory M2
macrophages and M2-like TAMs in BL exhibit an altered vitamin D metabolism, resulting in a reduced production of cathelicidin
and consequently in inability to lyse BL cells. However, treatment of M2 macrophages with the bioactive form of vitamin D,
1,25D3, or a vitamin D receptor agonist effectively induces cathelicidin production and triggers tumoricidal activity against
BL cells. Furthermore, rituximab-mediated cytotoxicity of vitamin D–treated M2 macrophages is cathelicidin-dependent. Finally,
vitamin D treatment of 25-hydroxyvitamin D (25D)–deficient volunteers in vivo or primary TAMs in vitro improves rituximab-mediated
ADCC against B cell lymphoma cells. These data indicate that activation of the vitamin D signaling pathway activates antitumor
activity of TAMs and improves the efficacy of ADCC.

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