The M1 Subtype Predominates among Infiltrating Tumor-Associated Macrophages in Phenotypically Aggressive Vestibular Schwannoma

Introduction: The vestibular schwannoma (VS) immune microenvironment has generated considerable interest as a potential avenue for targeted therapies. Tumor-associated macrophages (TAMs) have been implicated as pathologic actors in phenotypically aggressive VS, potentially via a hypothesized mechanism of immune evasion.

Methods: Forty-six consecutive, radiation-naive, sporadic VSs that underwent subtotal resection (STR) at primary surgery were assessed via immunohistochemical analysis, including CD163 and PD-L1. 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-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 grades I–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 grades III–VI facial nerve function (1 vs. 38%, p = 0.02). On multivariate analysis, PD-L1 was independently significant in all models (LR = 4.4, p = 0.04), while CD163 was dependent in all iterations.

Conclusion: In contrast to prior reports, we observed significantly increased levels of M1, CD163+ TAMs in association with VS that progressed after STR, or that had an unfavorable facial nerve outcome. These more aggressive tumors are also characterized by increased PD-L1, likely a mechanism of immune-evasion, which results in TAM deactivation, tumor growth, and further infiltration of additional anti-tumor immune cells. We anticipate that targeting the PD-1/PD-L1 axis may yield promising results, particularly in the setting of disease control after STR, and recommend further investigations in human and animal models regarding the potential efficacy of these immunomodulatory agents.

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