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.
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.
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.
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.
ABBREVIATIONSIHC = immunohistochemistry; LR = likelihood ratio; NF2 = neurofibromatosis type 2; PD-1 = programmed cell death protein 1; PD-L1 = programmed death-ligand 1; ROI = region of interest; SRS = stereotactic radiosurgery; STR = subtotal resection; TAM = tumor-associated macrophage; VS = vestibular schwannoma.
Correspondence Michael J. Link: Mayo Clinic, Rochester, MN. email@example.com.INCLUDE WHEN CITING Published online October 4, 2019; DOI: 10.3171/2019.7.JNS19879.Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
AhmadRA, SivalingamS, TopsakalV, RussoA, TaibahA, SannaM: Rate of recurrent vestibular schwannoma after total removal via different surgical approaches. 121:156–161, 201210.1177/00034894121210030322530474)| false
AllavenaP, SicaA, GarlandaC, MantovaniA: The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance. 222:155–161, 20081836400010.1111/j.1600-065X.2008.00607.x)| false
BergenfelzCLarssonAMvon StedingkKGruvberger-SaalSAaltonenKJanssonS: Systemic monocytic-MDSCs are generated from monocytes and correlate with disease progression in breast cancer patients. PLoS One10:e01270282015
BergenfelzC, LarssonAM, von StedingkK, Gruvberger-SaalS, AaltonenK, JanssonS, : Systemic monocytic-MDSCs are generated from monocytes and correlate with disease progression in breast cancer patients. 10:e0127028, 20152599261110.1371/journal.pone.0127028)| false
BlochOLimMSughrueMEKomotarRJAbrahamsJMO’RourkeDM: Autologous heat shock protein peptide vaccination for newly diagnosed glioblastoma: impact of peripheral PD-L1 expression on response to therapy. Clin Cancer Res23:3575–35842017
BystromJ, EvansI, NewsonJ, StablesM, ToorI, van RooijenN, : Resolution-phase macrophages possess a unique inflammatory phenotype that is controlled by cAMP. 112:4117–4127, 20081877939210.1182/blood-2007-12-129767)| false
de VriesM, Briaire-de BruijnI, MalessyMJ, de BruïneSF, van der MeyAG, HogendoornPC: Tumor-associated macrophages are related to volumetric growth of vestibular schwannomas. 34:347–352, 201310.1097/MAO.0b013e31827c9fbf)| false
de VriesMHogendoornPCBriaire-de BruynIMalessyMJvan der MeyAG: Intratumoral hemorrhage, vessel density, and the inflammatory reaction contribute to volume increase of sporadic vestibular schwannomas. Virchows Arch460:629–6362012
de VriesM, HogendoornPC, Briaire-de BruynI, MalessyMJ, van der MeyAG: Intratumoral hemorrhage, vessel density, and the inflammatory reaction contribute to volume increase of sporadic vestibular schwannomas. 460:629–636, 201210.1007/s00428-012-1236-9)| false
EdinSWikbergMLDahlinAMRutegårdJÖbergÅOldenborgPA: The distribution of macrophages with a M1 or M2 phenotype in relation to prognosis and the molecular characteristics of colorectal cancer. PLoS One7:e470452012
EdinS, WikbergML, DahlinAM, RutegårdJ, ÖbergÅ, OldenborgPA, : The distribution of macrophages with a M1 or M2 phenotype in relation to prognosis and the molecular characteristics of colorectal cancer. 7:e47045, 20122307754310.1371/journal.pone.0047045)| false
GraffeoCSPerryARaghunathanAKronemanTNJentoftMDriscollCL: Macrophage density predicts facial nerve outcome and tumor growth after subtotal resection of vestibular schwannoma. J Neurol Surg B Skull Base79:482–4882018
InagumaSWangZLasotaJSarlomo-RikalaMMcCuePAIkedaH: Comprehensive immunohistochemical study of programmed cell death ligand 1 (PD-L1): Analysis in 5536 cases revealed consistent expression in trophoblastic tumors. Am J Surg Pathol40:1133–11422016
IshidaY, AgataY, ShibaharaK, HonjoT: Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. 11:3887–3895, 1992139658210.1002/j.1460-2075.1992.tb05481.x)| false
IwaiYIshidaMTanakaYOkazakiTHonjoTMinatoN: Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A99:12293–122972002
IwaiY, IshidaM, TanakaY, OkazakiT, HonjoT, MinatoN: Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. 99:12293–12297, 200210.1073/pnas.19246109912218188)| false
NguyenTTSchwartzEJWestRBWarnkeRAArberDANatkunamY: Expression of CD163 (hemoglobin scavenger receptor) in normal tissues, lymphomas, carcinomas, and sarcomas is largely restricted to the monocyte/macrophage lineage. Am J Surg Pathol29:617–6242005
NguyenTT, SchwartzEJ, WestRB, WarnkeRA, ArberDA, NatkunamY: Expression of CD163 (hemoglobin scavenger receptor) in normal tissues, lymphomas, carcinomas, and sarcomas is largely restricted to the monocyte/macrophage lineage. 29:617–624, 200510.1097/01.pas.0000157940.80538.ec15832085)| false
PrimaVKaliberovaLNKaliberovSCurielDTKusmartsevS: COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells. Proc Natl Acad Sci U S A114:1117–11222017
SamiiMMatthiesCTatagibaM: Management of vestibular schwannomas (acoustic neuromas): auditory and facial nerve function after resection of 120 vestibular schwannomas in patients with neurofibromatosis 2. Neurosurgery40:696–7061997
SamiiM, MatthiesC, TatagibaM: Management of vestibular schwannomas (acoustic neuromas): auditory and facial nerve function after resection of 120 vestibular schwannomas in patients with neurofibromatosis 2. 40:696–706, 199710.1097/00006123-199704000-000079092842)| false