Expression and prognostic impact of immune modulatory molecule PD-L1 in meningioma

Abstract

While immunotherapy may offer promising new approaches for high grade meningiomas, little is currently known of the immune landscape in meningiomas. We sought to characterize the immune microenvironment and a potentially targetable antigen mesothelin across WHO grade I-III cases of meningiomas, and how infiltrating immune populations relate to patient outcomes. Immunohistochemistry was performed on tissue microarrays constructed from 96 meningioma cases. The cohort included 16 WHO grade I, 62 WHO grade II, and 18 WHO grade III tumors. Immunohistochemistry was performed using antibodies against CD3, CD8, CD20, CD68, PD-L1, and mesothelin. Dual staining using anti-PD-L1 and anti-CD68 antibodies was performed, and automated cell detection and positive staining detection algorithms were utilized. Greater degree of PD-L1 expression was found in higher grade tumors. More specifically, higher grade tumors contained increased numbers of intratumoral CD68−, PD-L1+ cells (p = 0.022), but did not contain higher numbers of infiltrating CD68+, PD-L1+ cells (p = 0.30). Higher PD-L1+/CD68− expression was independently predictive of worse overall survival in our cohort when accounting for grade, performance status, extent of resection, and recurrence history (p = 0.014). Higher expression of PD-L1+/CD68− was also present in tumors that had undergone prior radiotherapy (p = 0.024). Approximately quarter of meningiomas overexpressed mesothelin to levels equivalent to those found in pancreatic carcinomas and malignant mesotheliomas. The association with poor survival outcomes in our study suggests that PD-L1 may play a significant biologic role in the aggressive phenotype of higher grade meningiomas. Thus, immunotherapeutic strategies such as checkpoint inhibition may have clinical utility in PD-L1 overexpressing meningiomas.

Immunosuppressive activity of tumor-infiltrating myeloid cells in patients with meningioma

“…Besides myeloid cells, we found that leukocyte infiltrate in meningioma biopsies contained also lymphocytes, constituted for the vast majority by T cells with almost 50% of CD8 C T cells, in line with previous results 18,19,23,24 and no differences were observed with tumor grading (data not shown), as shown by other studies. 19,24 However, in grade III meningiomas Du et al reported a significant decrease in the number of CD3 C T lymphocytes, both CD4 C and CD8 C , as compared to low-grade meningiomas, 23 thus suggesting that T cells are reduced in high-grade meningiomas.…”

“…The presence of tumor-associated macrophages in meningioma is in line with other studies. [14][15][16][17][18][19] Myeloid cells have been characterized by CD68 expression 14,19 together with CD14, HLA-DR and CD163 expression 15,17 and described as a heterogeneous population composed of round, oval, ameboid or ramified mononuclear cells with small, dense nuclei together with mononuclear cells with slight to marked vacuolation, 16 all morphologic characteristics that we found also in our cytospin evaluation. Differently from Domingues et al, 18 in our analyses we also observed a myeloid cell population with low expression of HLA-DR that morphologically corresponds to granulocytes.…”

“…Both studies instead underlined that PD-L1 was expressed by tumor cells and that its levels increased with the progression of the disease. 19,23 Moreover, Han et al 19 identified PD-L1 expression on CD68 ¡ tumor cells as an independent predictor of overall survival. We also found high levels of PD-L1 expression in CD45 ¡ tumor cells, with a trend to increase between grade I and II meningiomas, although these levels did not reach a statistical significance.…”

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

“…Moreover, a recent study in which patients with urothelial cancer were treated with the anti-PD-L1 agent, atezolizumab, showed that PD-L1 expression on tumor immune infiltrate was associated with improved clinical responses [6]. Intriguingly, both high-grade meningioma and high-grade glioma show increased rates of PD-L1 expression, suggesting that PD-L1 may correlate both with tumor aggressiveness and potential response to therapy [39, 40]. However, additional studies have shown that patients with PD-L1 negative tumors may also exhibit clinical responses to anti-PD-1 therapies [41, 42].…”

Recent Advances in Meningioma Immunogenetics

“…Within tumor cells, expression of PD-L1, the PD-1 receptor ligand, increases with WHO tumor grade (17,55,57,58). However, overall mRNA or protein levels, as analyzed by RT-PCR, ISH, IHC, and flow cytometry varies widely from study to study.…”