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NF2 mutation status and tumor mutational burden correlate with immune cell infiltration in meningiomas

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Abstract

Background

The tumor microenvironment is an emerging biomarker of underlying genomic heterogeneity and response to immunotherapy-based treatment regimens in solid malignancies. How tumor mutational burden influences the density, distribution, and presence of a localized immune response in meningiomas is unknown.

Methods

Representative hematoxylin and eosin slides were reviewed at 40X to assess for the density of inflammatory cells. Lymphocytes and macrophages were quantified in the following ordinal manner: 0 = not present, 1 = 1–25 cells present, and 2 = greater than 26 cells present. Immune cell infiltrate grade was scored for both scattered and aggregated distributions. Next generation targeted sequencing was performed on all meningiomas included in this study.

Results

One hundred and forty-five meningiomas were evaluated in this study. Lymphocytes were observed in both scattered (95.9%) and aggregated (21.4%) distributions. A total of 115 (79.3%) meningiomas had 1–25 scattered lymphocytes, and 24 (16.6%) had > 25 scattered lymphocytes, and 6 (4.1%) had no scattered lymphocytes. Twenty (13.8%) meningiomas had 1–25 aggregated lymphocytes. Eleven (7.6%) had > 25 aggregated lymphocytes and 114 (78.6%) had no aggregated lymphocytes. Six (4.1%) meningiomas had 1–25 aggregated macrophages, 5 (3.4%) had > 25 aggregated macrophages, and 134 (92.4%) had no aggregated macrophages. Density of aggregated lymphocytes and aggregated macrophages were associated with higher tumor grade, P = 0.0071 and P = 0.0068, respectively. Scattered lymphocyte density was not associated with meningioma grade. The presence of scattered lymphocytes was associated with increased tumor mutational burden. Meningiomas that did not have scattered lymphocytes had a mean number of single mutations of 2.3 ± 2.9, compared with meningiomas that had scattered lymphocytes, 6.9 ± 20.3, P = 0.03. NF2 mutations were identified in 59 (40.7%) meningiomas and were associated with increased density of scattered lymphocytes. NF2 mutations were seen in 0 (0%) meningiomas that did not have scattered lymphocytes, 46 (40.0%) meningiomas that had 1–25 scattered lymphocytes, and 13 (54.2%) meningiomas that had > 25 scattered lymphocytes, P = 0.046.

Conclusions

Our findings suggest that distribution of immune cell infiltration in meningiomas is associated with tumor mutational burden. NF2 mutational status was associated with an increasing density of scattered lymphocytes. As the role of immunotherapy in meningiomas continues to be elucidated with clinical trials that are currently underway, these results may serve as a novel biomarker of tumor mutational burden in meningiomas.

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References

  1. Hasseleid BF, Meling TR, Ronning P, Scheie D, Helseth E (2012) Surgery for convexity meningioma: simpson grade i resection as the goal: clinical article. J Neurosurg 117:999–1006. https://doi.org/10.3171/2012.9.Jns12294

    Article  PubMed  Google Scholar 

  2. Rogers L, Barani I, Chamberlain M et al (2015) Meningiomas: knowledge base, treatment outcomes, and uncertainties. A RANO review. J Neurosurg 122:4–23. https://doi.org/10.3171/2014.7.Jns131644

    Article  PubMed  PubMed Central  Google Scholar 

  3. Surov A, Gottschling S, Bolz J, Kornhuber M, Alfieri A, Holzhausen HJ, Abbas J, Kosling S (2013) Distant metastases in meningioma: an underestimated problem. J Neurooncol 112:323–327. https://doi.org/10.1007/s11060-013-1074-x

    Article  PubMed  Google Scholar 

  4. Palma L, Celli P, Franco C, Cervoni L, Cantore G (1997) Long-term prognosis for atypical and malignant meningiomas: a study of 71 surgical cases. J Neurosurg 86:793–800. https://doi.org/10.3171/jns.1997.86.5.0793

    Article  CAS  PubMed  Google Scholar 

  5. Nanda A, Vannemreddy P (2008) Recurrence and outcome in skull base meningiomas: do they differ from other intracranial meningiomas. Skull Base Off J North Am Skull Base Soc 18:243–252. https://doi.org/10.1055/s-2007-1016956

    Article  Google Scholar 

  6. Cho YA, Lee J, Oh JH, Chang HJ, Sohn DK, Shin A, Kim J (2017) Genetic variation in PPARGC1A may affect the role of diet-associated inflammation in colorectal carcinogenesis. Oncotarget 8:8550–8558. https://doi.org/10.18632/oncotarget.14347

    Article  PubMed  Google Scholar 

  7. Li J, Zhou Z, Zhang X et al (2017) Inflammatory Molecule, PSGL-1, deficiency activates macrophages to promote colorectal cancer growth through NFkappaB signaling. Mol Cancer Res MCR 15:467–477. https://doi.org/10.1158/1541-7786.Mcr-16-0309

    Article  CAS  PubMed  Google Scholar 

  8. Zhang H, Xu X (2017) Mutation-promoting molecular networks of uncontrolled inflammation. Tumour Biol J Int Soc Oncodev Biol Med. https://doi.org/10.1177/1010428317701310

    Article  Google Scholar 

  9. Rossi ML, Cruz Sanchez F, Hughes JT, Esiri MM, Coakham HB (1988) Immunocytochemical study of the cellular immune response in meningiomas. J Clin Pathol 41:314–319. https://doi.org/10.1136/jcp.41.3.314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Proctor DT, Huang J, Lama S, Albakr A, Van Marle G, Sutherland GR (2019) Tumor-associated macrophage infiltration in meningioma. Neuro-Oncol Adv. https://doi.org/10.1093/noajnl/vdz018

    Article  Google Scholar 

  11. Louis DN, Perry A, Reifenberger G et al (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820. https://doi.org/10.1007/s00401-016-1545-1

    Article  PubMed  Google Scholar 

  12. Pain M, Wang H, Lee E, Strahl M, Hamou W, Sebra R, Zhu J, Yong RL (2018) Treatment-associated TP53 DNA-binding domain missense mutations in the pathogenesis of secondary gliosarcoma. Oncotarget 9:2603–2621. https://doi.org/10.18632/oncotarget.23517

    Article  PubMed  Google Scholar 

  13. Gill CM, Loewenstern J, Rutland JW et al (2020) STK11 mutation status is associated with decreased survival in meningiomas. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol. https://doi.org/10.1007/s10072-020-04372-y

    Article  Google Scholar 

  14. Gill CM, Loewenstern J, Rutland JW et al (2020) Recurrent IDH mutations in high-grade meningioma. Neuro-oncology. https://doi.org/10.1093/neuonc/noaa065

    Article  PubMed  PubMed Central  Google Scholar 

  15. Gill CM, Loewenstern J, Rutland JW et al (2020) In reply: retention of ATRX and DAXX expression in meningiomas. Neurosurgery 86:E244–E246. https://doi.org/10.1093/neuros/nyz504

    Article  PubMed  Google Scholar 

  16. Loewenstern J, Rutland J, Gill C et al (2019) Comparative genomic analysis of driver mutations in matched primary and recurrent meningiomas. Oncotarget 10:3506–3517. https://doi.org/10.18632/oncotarget.26941

    Article  PubMed  PubMed Central  Google Scholar 

  17. Clark VE, Harmancı AS, Bai H et al (2016) Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas. Nat Genet 48:1253–1259. https://doi.org/10.1038/ng.3651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Clark VE, Erson-Omay EZ, Serin A et al (2013) Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science 339:1077–1080. https://doi.org/10.1126/science.1233009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gupta S, Bi WL, Dunn IF (2018) Medical management of meningioma in the era of precision medicine. Neurosurg Focus 44:E3. https://doi.org/10.3171/2018.1.Focus17754

    Article  PubMed  Google Scholar 

  20. Johnson LA, Sampson JH (2010) Immunotherapy approaches for malignant glioma from 2007 to 2009. Curr Neurol Neurosci Rep 10:259–266. https://doi.org/10.1007/s11910-010-0111-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Prins RM, Soto H, Konkankit V, Odesa SK, Eskin A, Yong WH, Nelson SF, Liau LM (2011) Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin Cancer Res Off J Am Assoc Cancer Res 17:1603–1615. https://doi.org/10.1158/1078-0432.Ccr-10-2563

    Article  CAS  Google Scholar 

  22. Brastianos PK, Galanis E, Butowski N et al (2019) Advances in multidisciplinary therapy for meningiomas. Neuro-oncology 21:i18–i31. https://doi.org/10.1093/neuonc/noy136%JNeuro-Oncology

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Grund S, Schittenhelm J, Roser F, Tatagiba M, Mawrin C, Kim YJ, Bornemann A (2009) The microglial/macrophagic response at the tumour-brain border of invasive meningiomas. Neuropathol Appl Neurobiol 35:82–88. https://doi.org/10.1111/j.1365-2990.2008.00960.x

    Article  CAS  PubMed  Google Scholar 

  24. Becker I, Roggendorf W (1989) Immunohistological investigation of mononuclear cell infiltrates in meningiomas. Acta Neuropathol 79:211–216

    Article  CAS  PubMed  Google Scholar 

  25. Rapp C, Dettling S, Liu F et al (2019) Cytotoxic T cells and their activation status are independent prognostic markers in meningiomas. Clin Cancer Res Off J Am Assoc Cancer Res 25:5260–5270. https://doi.org/10.1158/1078-0432.Ccr-19-0389

    Article  CAS  Google Scholar 

  26. Liu F, Lang R, Zhao J et al (2011) CD8(+) cytotoxic T cell and FOXP3(+) regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes. Breast Cancer Res Treat 130:645–655. https://doi.org/10.1007/s10549-011-1647-3

    Article  CAS  PubMed  Google Scholar 

  27. Schalper KA, Brown J, Carvajal-Hausdorf D, McLaughlin J, Velcheti V, Syrigos KN, Herbst RS, Rimm DL (2015) Objective measurement and clinical significance of TILs in non-small cell lung cancer. J Natl Cancer Inst. https://doi.org/10.1093/jnci/dju435

    Article  PubMed  PubMed Central  Google Scholar 

  28. Han SJ, Reis G, Kohanbash G et al (2016) Expression and prognostic impact of immune modulatory molecule PD-L1 in meningioma. J Neurooncol 130:543–552. https://doi.org/10.1007/s11060-016-2256-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Li YD, Veliceasa D, Lamano JB, Lamano JB, Kaur G, Biyashev D, Horbinski CM, Kruser TJ, Bloch O (2019) Systemic and local immunosuppression in patients with high-grade meningiomas. Cancer Immunol Immunother CII 68:999–1009. https://doi.org/10.1007/s00262-019-02342-8

    Article  CAS  PubMed  Google Scholar 

  30. Giles AJ, Hao S, Padget M et al (2019) Efficient ADCC killing of meningioma by avelumab and a high-affinity natural killer cell line, haNK. JCI Insight. https://doi.org/10.1172/jci.insight.130688

    Article  PubMed  PubMed Central  Google Scholar 

  31. Du Z, Abedalthagafi M, Aizer AA et al (2015) Increased expression of the immune modulatory molecule PD-L1 (CD274) in anaplastic meningioma. Oncotarget 6:4704–4716. https://doi.org/10.18632/oncotarget.3082

    Article  PubMed  Google Scholar 

  32. Han SJ, Reis G, Kohanbash G et al (2016) Expression and prognostic impact of immune modulatory molecule PD-L1 in meningioma. J Neuro-Oncology 130:543–552. https://doi.org/10.1007/s11060-016-2256-0

    Article  CAS  Google Scholar 

  33. Erkan EP, Ströbel T, Dorfer C, Sonntagbauer M, Weinhäusel A, Saydam N, Saydam O (2019) Circulating tumor biomarkers in meningiomas reveal a signature of equilibrium between tumor growth and immune modulation. Front Oncol. https://doi.org/10.3389/fonc.2019.01031

    Article  PubMed  PubMed Central  Google Scholar 

  34. Keren L, Bosse M, Marquez D et al (2018) A structured tumor-immune microenvironment in triple negative breast cancer revealed by multiplexed ion beam imaging. Cell 174:1373–87.e19. https://doi.org/10.1016/j.cell.2018.08.039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, Stephens PJ, Daniels GA, Kurzrock R (2017) Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther 16:2598–2608. https://doi.org/10.1158/1535-7163.Mct-17-0386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hugo W, Zaretsky JM, Sun L et al (2016) Genomic and transcriptomic features of response to Anti-PD-1 therapy in metastatic melanoma. Cell 165:35–44. https://doi.org/10.1016/j.cell.2016.02.065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dunn IF, Du Z, Touat M et al (2018) Mismatch repair deficiency in high-grade meningioma: a rare but recurrent event associated with dramatic immune activation and clinical response to PD-1 blockade. JCO Precis Oncol. https://doi.org/10.1200/po.18.00190

    Article  PubMed  PubMed Central  Google Scholar 

  38. McGranahan T, Therkelsen KE, Ahmad S, Nagpal S (2019) Current state of immunotherapy for treatment of glioblastoma. Curr Treat Option Oncol 20:24. https://doi.org/10.1007/s11864-019-0619-4

    Article  Google Scholar 

  39. Snyder A, Makarov V, Merghoub T et al (2014) Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371:2189–2199. https://doi.org/10.1056/NEJMoa1406498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rizvi NA, Hellmann MD, Snyder A et al (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124–128. https://doi.org/10.1126/science.aaa1348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gelerstein E, Berger A, Jonas-Kimchi T et al (2017) Regression of intracranial meningioma following treatment with nivolumab: case report and review of the literature. J Clin Neurosci Off J Neurosurg Soc Australas 37:51–53. https://doi.org/10.1016/j.jocn.2016.11.011

    Article  Google Scholar 

  42. Ding Y, Qiu L, Xu Q, Song L, Yang S, Yang T (2014) Relationships between tumor microenvironment and clinicopathological parameters in meningioma. Int J Clin Exp Pathol 7:6973–6979

    PubMed  PubMed Central  Google Scholar 

  43. Fang L, Lowther DE, Meizlish ML et al (2013) The immune cell infiltrate populating meningiomas is composed of mature, antigen-experienced T and B cells. Neuro-oncology 15:1479–1490. https://doi.org/10.1093/neuonc/not110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pearson BE, Markert JM, Fisher WS, Guthrie BL, Fiveash JB, Palmer CA, Riley K (2008) Hitting a moving target: evolution of a treatment paradigm for atypical meningiomas amid changing diagnostic criteria. Neurosurg Focus 24:E3. https://doi.org/10.3171/foc/2008/24/5/e3

    Article  PubMed  Google Scholar 

  45. Simon M, Bostrom J, Koch P, Schramm J (2006) Interinstitutional variance of postoperative radiotherapy and follow up for meningiomas in Germany: impact of changes of the WHO classification. J Neurol Neurosurg Psychiatry 77:767–773. https://doi.org/10.1136/jnnp.2005.077974

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

John Rutland was supported by the Rare diseases foundation and the BC Children’s Hospital Foundation.

Funding

This study was internally funded by the Icahn School of Medicine at Mount Sinai.

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Author notes

  1. John W. Rutland and Corey M. Gill contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Icahn School of Medicine At Mount Sinai, 1468 Madison Avenue; Floor 8, New York, NY, 10129, USA

    John W. Rutland, Corey M. Gill, Joshua Loewenstern, Margaret Pain, Joshua Bederson & Raj K. Shrivastava

  2. Department of Genetics and Genomic Sciences, Icahn School of Medicine At Mount Sinai, New York, NY, USA

    Hanane Arib & Robert Sebra

  3. Department of Pathology, Icahn School of Medicine At Mount Sinai, New York, NY, USA

    Melissa Umphlett, Yayoi Kinoshita, Russell B. McBride, Michael Donovan & Mary Fowkes

  4. The Institute for Translational Epidemiology, Icahn School of Medicine At Mount Sinai, New York, NY, USA

    Russell B. McBride

  5. Sema4, A Mount Sinai Venture, Stamford, CT, USA

    Robert Sebra

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  1. John W. Rutland
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Contributions

JWR—manuscript drafting, data collection, critical revision, reviewed final manuscript, and submitted on behalf of the authors; CMG—manuscript drafting, statistical analysis, and reviewed final manuscript; JL—data collection, data analysis, and reviewed final manuscript; HA—data analysis and reviewed final manuscript; MP—data analysis and reviewed final manuscript; MU—data analysis and reviewed final manuscript; YK—data analysis and reviewed final manuscript; RBM—data analysis and reviewed final manuscript; JB—data analysis and reviewed final manuscript; MD—data analysis and reviewed final manuscript; RS—reviewed final manuscript and data analysis; RKS—reviewed final manuscript, study supervision, and critical revision; MF—data collection, reviewed final manuscript, study supervision, and critical revision.

Corresponding author

Correspondence to John W. Rutland.

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Conflicts of interest

Dr. Joshua Bederson (a Significant Contributor in this study and Chair of the Department of Neurosurgery) owns equity in Surgical Theater, LLC [manufacturer of the Surgical Navigation Advanced Platform (SNAP) system that may be used for intraoperative image guidance in the study]. The remaining authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Ethical approval

This study was by the Icahn School of Medicine at Mount Sinai Institutional Review Board, and we certify that the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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Rutland, J.W., Gill, C.M., Loewenstern, J. et al. NF2 mutation status and tumor mutational burden correlate with immune cell infiltration in meningiomas. Cancer Immunol Immunother 70, 169–176 (2021). https://doi.org/10.1007/s00262-020-02671-z

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