Stratifying nonfunctional pituitary adenomas into two groups distinguished by macrophage subtypes

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.

Efficacy of pembrolizumab in patients with pituitary carcinoma: report of four cases from a phase II study

“…One study that analyzed CD11b-expressing cells (expressed on monocytes, neutrophils, natural killer cells, granulocytes and macrophages) in 16 non-functioning pituitary tumors demonstrated that a higher proportion of CD11 + cells (>10%) was associated with a more expansile and mitotically active tumor. 21 This study also demonstrated that tumors invading the cavernous sinus had a greater presence of immunosuppressive macrophages (M2) than did non-invasive tumors (M2/M1 ratio >1 vs M2/M1 ratio <1). The correlation between increased number of immunosuppressive M2 macrophages and invasive behavior has been described in many cancer types.…”

Lactate-induced M2 polarization of tumor-associated macrophages promotes the invasion of pituitary adenoma by secreting CCL17

“…TAMs can contribute to tumor invasion by promoting tumor cell proliferation, EMT, and invasion as well as suppressing tumoricidal immune cells 8 , 39 , 40 . The important role of TAMs in pituitary tumors has also been highlighted in two other studies 41 , 42 . A variety of cytokines, chemokines, and other immune mediators is secreted by macrophages during immune responses, which serves as a means of intracellular communication 43 .…”

Evaluating the Polarization of Tumor-Associated Macrophages Into M1 and M2 Phenotypes in Human Cancer Tissue: Technicalities and Challenges in Routine Clinical Practice

“…Higher infiltration of the M2 TAMs is associated with a more aggressive tumor characteristic, reflected by tumor invasion, progression, and metastases. A recent study on non-functional pituitary adenomas (NFPAs) discovered that the cultured M2 macrophages significantly enhanced the proliferation and invasion of the primary NFPA cultures as compared to the cultured M1 macrophages (20). In hepatocellular carcinoma, higher M2 TAMs were strongly correlated with more tumor number and advanced stages (21).…”