Abstract
The histological architecture of certain aggressive B-cell lymphomas (prototypically Burkitt's lymphoma, BL) is characterized by a “starry-sky” (SS) appearance. This is caused by tumor-associated macrophages (TAMs), which appear in standard histological preparations as “stars” in a darkly stained “sky” of lymphoma cells. SS-TAMs accumulate in response to constitutive apoptosis in these tumors and are activated by the apoptotic tumor cells to a pro-oncogenic phenotype. The extent to which SS-TAMs contribute to lymphoma growth through responses generated by interactions with apoptotic tumor cells is unknown. Here, we demonstrate a role for the receptor tyrosine kinase, MERTK, in the oncogenic activity of SS-TAMs. We show that MERTK expression is largely restricted to the macrophages of human BL and of murine models of SS B-cell lymphoma and that it is upregulated in SS-TAMs as compared to the germinal center or paracortical macrophages of normal lymph nodes. Our results further demonstrate that MERTK is active in the phagocytosis of apoptotic lymphoma cells by macrophages and, most significantly, that SS lymphoma growth is markedly inhibited in Mertk−/− mice. These results point toward the MERTK apoptotic-cell clearance/response pathway playing a key role in growth of aggressive B-cell lymphoma and identifies MERTK as a novel potential antilymphoma target.
Highlights
Constitutive tumor-cell apoptosis is high in aggressive cancers, including non-Hodgkin lymphoma [1]
In SS lymphomas, apoptosis is highly prominent in standard biopsy preparations, and a key response to apoptotic tumor cells is the accumulation of tumor-associated macrophages (TAMs), together with their activation to a pro-oncogenic phenotype [5]
Absence of MERTK protein expression by murine lymphoma cells was confirmed by flow cytometry (Figure 1B), by immunoblotting (Supplementary Figure 1A) and by real-time RT-PCR (Supplementary Figure 1B)
Summary
Constitutive tumor-cell apoptosis is high in aggressive cancers, including non-Hodgkin lymphoma [1]. Emerging evidence indicates that responses to apoptosis in the tumor microenvironment can promote cancer growth, in primary tumors, and in post-therapeutic relapse [2,3,4,5,6,7]. In SS lymphomas, apoptosis is highly prominent in standard biopsy preparations, and a key response to apoptotic tumor cells is the accumulation of TAMs, together with their activation to a pro-oncogenic phenotype [5]. It remains unclear how apoptotic tumor cells activate TAMs to help promote net tumor growth. We focus on MERTK, a member of the TYRO3/AXL/MERTK family of receptor tyrosine kinases, which regulate tissue development and homeostasis via two mechanistically related immunosuppressive functions: the clearance of cells undergoing apoptosis and anti-inflammatory signaling [8,9,10].
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