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

Abstract

PurposeSubsets of pituitary tumors exhibit an aggressive clinical courses and recur despite surgery, radiation, and chemotherapy. Because modulation of the immune response through inhibition of T-cell checkpoints has led to durable clinical responses in multiple malignancies, we explored whether pituitary adenomas express immune-related biomarkers that could suggest suitability for immunotherapy. Specifically, programmed death ligand 1 (PD-L1) has emerged as a potential biomarker whose expression may portend more favorable responses to immune checkpoint blockade therapies. We thus investigated the expression of PD-L1 in pituitary adenomas.MethodsPD-L1 RNA and protein expression were evaluated in 48 pituitary tumors, including functioning and non-functioning adenomas as well as atypical and recurrent tumors. Tumor infiltrating lymphocyte populations were also assessed by immunohistochemistry.ResultsPituitary tumors express variable levels of PD-L1 transcript and protein. PD-L1 RNA and protein expression were significantly increased in functioning (growth hormone and prolactin-expressing) pituitary adenomas compared to non-functioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary adenomas harbored higher levels of PD-L1 mRNA compared to recurrent tumors. Tumor infiltrating lymphocytes were observed in all pituitary tumors and were positively correlated with increased PD-L1 expression, particularly in the functional subtypes.ConclusionsHuman pituitary adenomas harbor PD-L1 across subtypes, with significantly higher expression in functioning adenomas compared to non-functioning adenomas. This expression is accompanied by the presence of tumor infiltrating lymphocytes. These findings suggest the existence of an immune response to pituitary tumors and raise the possibility of considering checkpoint blockade immunotherapy in cases refractory to conventional management.

MANAGEMENT OF ENDOCRINE DISEASE: Immune check point inhibitors-induced hypophysitis

“…As IgG4 cannot activate the complement pathway and is less effective for antibody-dependent cell-mediated cytotoxicity, the pathogenesis of the few anti-PD-1 or PD-L1-induced cases of hypophysitis is not clear. PD-1 could be expressed in pituitary cells or lymphocytes, as PD-L1 is expressed in pituitary adenomas (37) or as these antibodies are IgG4, they should share the same mechanism as IgG4-related hypophysitis (38).…”

Invited Review: Pathology of pituitary neuroendocrine tumours: present status, modern diagnostic approach, controversies and future perspectives from a neuropathological and clinical standpoint

“…Novilumab) . CTLA‐4 expression has been demonstrated on pituitary endocrine cells , and PDL‐1 transcript and protein have been demonstrated in different subtypes of PitNETs . A recent case report demonstrated a significant response to immune checkpoint inhibitors, ipilimumab and nivolumab, in a patient with a hypermutated temozolomide‐resistant corticotroph carcinoma .…”

Exploring the Role of Novel Medical Therapies for Aggressive Pituitary Tumors: A Review of the Literature—“Are We There Yet?”

“…Pituitary tumors have been demonstrated to express PD-L1 and CD8+ tumor-infiltrating lymphocytes with higher PD-L1 expression in functioning adenomas and a correlation between PD-L1 expression, hormone levels, and Ki67 [123][124][125]. These findings provide a rationale for exploring the role of immunotherapy in the management of APTs.…”