Tumor-associated macrophages (TAMs) polarize to M1 and M2 subtypes exerting anti-tumoral
and protumoral effects, respectively. To date, little is known about TAMs, their subtypes,
and their roles in nonfunctional pituitary adenomas (NFPAs). We performed flow cytometry
on single cell suspensions from 16 NFPAs, revealing CD11b+ myeloid cells to 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.
