Predominance of M1 subtype among tumor-associated macrophages in phenotypically aggressive sporadic vestibular schwannoma

Objective: Tumor-associated macrophages (TAMs) have been implicated as pathologic actors in phenotypically aggressive vestibular schwannoma (VS), potentially mediated via programmed death-ligand 1 (PD-L1). The authors hypothesized that PD-L1 is a key regulator of the VS immune microenvironment.

Methods: Forty-six consecutive, radiation-naïve, sporadic VSs that were subtotally resected at primary surgery were assessed via immunohistochemical analysis, including analysis of CD163 and PD-L1 expression. Pathologic data were correlated with clinical endpoints, including tumor control, facial nerve function, and complications.

Results: Baseline parameters were equivalent between stable and progressive post-subtotal resection (STR) VS. CD163 percent positivity and M2 index were significantly increased among tumors that remained stable (34% vs 21%, p = 0.02; 1.13 vs 0.99, p = 0.0008), as well as patients with favorable House-Brackmann grade I or II facial nerve function (31% vs 13%, p = 0.04; 1.11 vs 0.97, p = 0.05). PD-L1 percent positivity was significantly associated with tumor progression (1% vs 11%, p = 0.01) and unfavorable House-Brackmann grade III-VI facial nerve function (1% vs 38%, p = 0.02). On multivariate analysis, PD-L1 was independently significant in all models (likelihood ratio 4.4, p = 0.04), while CD163 was dependent in all iterations.

Conclusions: In contrast to prior reports, in this study, the authors observed significantly increased levels of M1, CD163+ TAMs in association with VS that progressed after STR. Progressive tumors are characterized by increased PD-L1, potentially highlighting a mechanism of immune evasion that results in TAM deactivation, tumor growth, and further infiltration of anti-tumor immune cells. Targeting PD-1/PD-L1 may offer therapeutic promise, particularly in the setting of disease control after STR.