Immune Microenvironment of Pituitary Adenomas

Background Pituitary tumors are the second most common primary brain tumors. We previously demonstrated that hormone-secreting, or functional, adenomas may host a suppressed immune surveillance state, as evidenced by increased expression of the immune checkpoint marker PD-L1. We hypothesized that pituitary adenomas exhibit a variable immune signature which may influence their behavior, and sought to profile an expanded cohort of immune regulatory markers to better characterize their immune microenvironment.

Method Seventy-two pituitary adenomas were evaluated for expression of the immune regulatory markers PD-L1, VISTA, and OX40 by immunohistochemistry, as well as for lymphocytes infiltration by the T cell markers CD8 and FOXP3, and the macrophage markers CD163, CD68, and CD45. LAG3, a marker of T cell exhaustion was also assessed.

Results We observed a prominent immune cell infiltrate, as defined by high expression of T cell or macrophage markers, in 40% of tumors. In addition, we observed high expression of the immune regulatory markers, PD-L1, VISTA, LAG3, and OX40 in 60% of adenomas. Interestingly, these markers were differentially elevated in different subset of tumors, with near exclusivity between those adenomas with high expression of OX40 and VISTA. Forty percent of the adenomas were functional tumors; 11% were recurrent. Extent of macrophage infiltration was comparable between functional and nonfunctional adenomas. T cell infiltration, as indicated by CD8 and FOXP3 expression, was significantly increased in functional tumors with increased expression of the T cell exhaustion marker LAG3. In addition, functional adenomas had increased expression of the negative immune checkpoint regulators, PD-L1 and VISTA, along with reduced expression of the T cell activation marker OX40. Within functional adenomas, PD-L1 correlated to the T regulatory cell marker FOXP3, while expression of VISTA correlated with the macrophage marker CD68. Primary adenomas expressed higher level of PD-L1 and LAG3 compared with recurrent adenomas.

Conclusion We demonstrate a significant and variable presence of immune infiltrates and regulatory proteins within pituitary adenomas. Immune escape was more prominent in functional and primary pituitary adenomas. The presence of different immune checkpoint markers in distinct pituitary adenoma populations calls for novel therapeutic strategies that account for such diversity of immune regulation.

No conflict of interest has been declared by the author(s).