Tumor-Associated Macrophage Expression of PD-L1 Is Associated with Recurrence after Subtotal Resection of Vestibular Schwannoma

Background Progression after subtotal resection (STR) is a common management challenge in vestibular schwannomas (VS) surgery, affecting up to 40% of STR patients. Identification of novel markers for tumor aggressiveness is a key scientific goal, both to enhance targeted delivery of individualized therapies and to avoid unnecessary or premature initiation of adjuvant treatment. Prior authors including our group have demonstrated the critical importance of integrating an understanding of tumor-associated macrophages (TAMs) into the treatment paradigm—particularly given the recently established link between TAMS, aggressive non-neurologic neoplasms, and poor overall prognoses. TAMs express programmed cell death 1 receptor, an immune checkpoint inhibitor that, when bound with the ligand PD-L1, negates antitumor phagocytosis. Previous investigations have shown that VSs are extensively infiltrated by TAMs; correspondingly, our goal was to characterize for the first time the extent of PD-L1 expression in macrophage-laden VS, and to assess their interrelatedness with respect to tumor progression and aggressiveness.

Methods Forty-one consecutive VS patients who underwent STR by a single surgeon (M.J.L.) at our institution were included. Clinical endpoints including tumor progression, postoperative facial nerve function, and cerebrospinal fluid (CSF) leak were abstracted from a prospectively maintained institutional VS database. Pathologic specimens were stained for PD-L1 and standard markers of proliferating cells, macrophages, or Schwann cells, which were then quantitated via digital imaging analysis.

Results Among 41 STR patients, 11 progressed during the study period (27%), and cytoplasmic PD-L1 percent positivity was noted to be significantly higher in those patients who progressed (median: 1 vs. 10%, p = 0.03). Postoperative CSF leak occurred in five patients (12%), among whom cytoplasmic PD-L1 staining was noted to be significantly increased (median: 12 vs. 44%, p = 0.02). As of last follow-up, unfavorable facial nerve function (House-Brackmann 3–6) persisted in eight patients (19%), a poor outcome that was also significantly associated with increased cytoplasmic PD-L1 staining (median 9 vs. 40%, p = 0.04).

Conclusion PD-L1 is expressed in most VSs, but appears to be significantly overexpressed in a higher risk phenotype, and may be a marker for a more invested, challenging-to-resect tumor, given the significant associations we observed between PD-L1 and tumor progression, CSF leak, and unfavorable facial nerve outcomes. This relationship emphasizes the importance of PD-1 as a druggable target with considerable potential in VS medical management, with multiple FDA-approved agents available for trial on an off-label basis in both sporadic and hereditary VS populations. Although much remains to be learned regarding the role of PD-L1 in particular and the immune system in general in VS surgery, the current results offer an important advance on our preceding work, and present novel insight into a possible mechanism of TAM-associated tumor progression.