Abstract
Tumor-associated macrophages (TAMs) polarize to M1 and M2 subtypes exerting anti-tumoral and pro-tumoral effects, respectively. To date, little is known about TAMs, their subtypes, and their roles in non-functional pituitary adenomas (NFPAs). We performed flow cytometry on single cell suspensions from 16 NFPAs, revealing that CD11b+ myeloid cells comprise an average of 7.3% of cells in NFPAs (range = 0.5%–27.1%), with qPCR revealing most CD11b+ cells to be monocyte-derived TAMs rather than native microglia. The most CD11b-enriched NFPAs (10–27% CD11b+) were the most expansile (size>3.5 cm or MIB1>3%). Increasing CD11b+ fraction was associated with decreased M2 TAMs and increased M1 TAMs. All NFPAs with cavernous sinus invasion had M2/M1 gene expression ratios above one, while 80% of NFPAs without cavernous sinus invasion had M2/M1<1 (P = 0.02). Cultured M2 macrophages promoted greater invasion (P < 10-5) and proliferation (P = 0.03) of primary NFPA cultures than M1 macrophages in a manner inhibited by siRNA targeting S100A9 and EZH2, respectively. Primary NFPA cultures were of two types: some recruited more monocytes in an MCP-1-dependent manner and polarized these to M2 TAMs, while others recruited fewer monocytes and polarized them to M1 TAMS in a GM-CSF-dependent manner. These findings suggest that TAM recruitment and polarization into the pro-tumoral M2 subtype drives NFPA proliferation and invasion. Robust M2 TAM infiltrate may occur during an NFPA growth phase before self-regulating into a slower growth phase with fewer overall TAMs and M1 polarization. Analyses like these could generate immunomodulatory therapies for NFPAs.
Highlights
Non-functional pituitary adenomas (NFPAs) are among the most common primary brain tumors [1]
We found that the percentage of cells in non-functional pituitary adenomas (NFPAs) that were CD11b+ did not vary regionally between the medial versus lateral aspects of the tumor (Figure 1C; Supplementary Figure 2), further validating the choice of this approach
M2 Tumor-associated macrophages (TAMs) proved to be a source of the MCP-1 suppression we noted in the presence of increasing TAMs (Figure 1F) as we found that conditioned media (CM) from M2 macrophages reduced MCP-1 expression in cultured NFPA cells compared to CM from M1 macrophages (Figure 2E; P < 0.01)
Summary
Non-functional pituitary adenomas (NFPAs) are among the most common primary brain tumors [1]. While histologically benign, they radiographically and clinically range from slow growing, incidentally found tumors to more aggressive versions that can exert a devastating impact on a patient’s quality of life through mass effect on neuroanatomical structures causing hypopituitarism [2], vision loss [3], and debilitating headaches [4]. While several studies have defined molecular alterations in NFPA cells [5,6,7], very few studies have investigated the immune microenvironment in NFPAs. One large study found that lymphocytic infiltrates are very rare in NFPAs and functional pituitary adenomas [8]. The ability of PD-L1 to allow cancers to escape T cell-mediated immune responses could explain the lack of lymphocytic infiltrates in pituitary adenomas
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