Vitamin D–dependent induction of cathelicidin in human macrophages results in cytotoxicity against high-grade B cell lymphoma

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.

The Role of Vitamin D in the Immune System as a Pro-survival Molecule

“…Vitamin D deficiency might be a great concern even for cancer, as calcitriol contributes to enhancing the antitumoral action of innate immune cells. 109 These observations may raise criticism about the pro-survival role exerted by vitamin D, while its healthy potential closely depends on the good performance of the organism's homeostatic machinery.…”

Progress in tumor-associated macrophage (TAM)-targeted therapeutics

“…In another example, macrophages may secrete a host-defense peptide, cathelicidin, shown to readily lyse proliferating B cell lymphoma cells but not normal B cells [146]. Cathelicidin production requires intracellular metabolism of 25-hydroxyvitamin D (25D) into bioactive 1,25-dihydroxyvitamin D (1,25D3) by vitamin D-1-hydroxylase CYP27B1, which is expressed at lower levels in M2 macrophages and TAMs compared to M1 macrophages.…”

Roles and Mechanisms of Human Cathelicidin LL-37 in Cancer

“…5) [90]. Another report also showed that the versican V1 derived from tumor cells enhances hCAP18/LL-37 expression in macrophages through the activation of TLR2 and subsequent vitamin D-dependent mechanisms to promote ovarian cancer progression in vitro [42].…”

“…Cathelicidin secreted from inflammatory M1 macrophages has been shown to directly induce cell death by targeting mitochondria of high-grade lymphatic malignancies such as Burkitt's lymphoma (BL) cells [90]. Conversely, anti-inflammatory M2 macrophages and M2-like tumor-associated macrophages (TAMs) in BL affect vitamin D signaling, resulting in downregulation of hCAP-18/LL-37 and consequently, in inability to kill BL cells (Fig.…”