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Vitamin D lends a helping hand
In theory, macrophages and other immune cells should be able to kill tumor cells. However, cancer cells are clearly capable of escaping from immune surveillance, and tumor-associated macrophages usually do not kill them, for reasons that are not yet well understood. A new study by Bruns et al. shows that vitamin D can help promote the antitumor activity of macrophages and stimulate their production of cathelicidin, an antimicrobial peptide that can also induce tumor cell death. The results suggest that for cancer patients who are deficient in vitamin D, providing vitamin D supplementation may be helpful in battling the disease and promoting the efficacy of antitumor therapy.
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.
- Copyright © 2015, American Association for the Advancement of Science
