Immune Cell Infiltrates in Pituitary Adenomas: More Macrophages in Larger Adenomas and More T Cells in Growth Hormone Adenomas

Abstract

Tumor immune microenvironment has been gradually recognized as a key contributor to tumor development, progression, and control. Immune cell infiltrates in brain tumors have been increasingly studied, but few have published on immune cell infiltrates in pituitary adenomas. We quantitatively assessed the infiltration of macrophages and lymphocytes in 35 pituitary adenomas, including 9 densely granulated growth hormone (DG-GH), 9 sparsely granulated growth hormone (SG-GH), 9 null cell (NC), and 8 adrenocorticotropic hormone (ACTH) adenomas. All the adenomas showed varying degrees of CD68+ macrophage infiltration. While SG-GH adenomas were significantly larger in size than DG-GH and ACTH adenomas, the infiltration of CD68+ macrophages was significantly greater in SG-GH than in DG-GH and ACTH adenomas. Similarly, NC adenomas that were significantly larger than DG-GH and ACTH adenomas had significantly greater infiltration of CD68+ macrophages than DG-GH and ACTH adenomas. The numbers of CD68+ macrophages were positively correlated with the tumor sizes and Knosp classification grades for tumor invasiveness. The infiltration of CD4+ and CD8+ T cells was relatively scant in these adenomas, but GH adenomas exhibited significantly more CD4+ and CD8+ T cells than non-GH adenomas. Both DG-GH and SG-GH adenomas had significantly more CD4+ cells than ACTH adenomas and significantly more CD8+ cells than NC adenomas. These results suggest an association of CD68+ macrophage infiltration with an increase in the pituitary adenoma size and invasiveness. Our observation contributes to understanding the growth environment of pituitary adenomas, for which adjuvant immunotherapy may help to constrain the tumor enlargement and invasiveness.

Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors

“…Functional subtypes (e.g. GH adenomas) appear to demonstrate greater degrees of lymphocyte infiltration than non-functional tumors [32]. In our study, functional pituitary tumors exhibited more frequent lymphocytic infiltration than non-functional tumors, consistent with previous observations [31].…”

Tumour-infiltrating cytotoxic T lymphocytes in somatotroph pituitary neuroendocrine tumours

“…A study on a cohort of 291 PitNET patients showed that TILs were more abundant in PitNETs compared with the normal pituitary gland and that TILs were associated with a poorer clinical outcome, although a pan-lymphocyte marker was employed, limiting further conclusions [33]. Another study on 35 PitNETs, including 18 somatotroph tumours, showed a positive correlation between the number of infiltrating CD68+ macrophages and tumour size and invasiveness [34]. In the same study, somatotroph tumours were shown to have a higher number of infiltrating CD4+ and CD8+ TILs compared with non-somatotroph tumours.…”

Detection of programmed death ligand 1 protein and CD8+ lymphocyte infiltration in plurihormonal pituitary adenomas

“…[ 16 ] Both the CD4 + and CD8 + lymphocytes were frequently observed in GH-secreting pituitary adenomas. [ 17 ] The inhibition of PD-1 signaling pathways could help CD8 + lymphocytes recognize and kill tumor cells. [ 15 , 18 ] Moreover, blockade of the PD-1 signaling pathways was also substantial for macrophages to inhibit tumor development.…”