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Tumor immune microenvironment in brain metastases from gynecologic malignancies

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Abstract

Introduction

The density and distribution of the tumor immune microenvironment associated with brain metastases (BM) from gynecologic malignancies are unknown and have not been previously reported. We sought to describe the clinical features of a cohort of patients with BM from gynecologic malignancies and to characterize the tumor immune microenvironment from available archival surgical specimens.

Methods

We performed a retrospective review of electronic medical records from 2002 to 2018 for patients with BM from gynecologic malignancies. Data on patient characteristics, treatment regimens, and clinical outcomes were procured. CD4, CD8, CD45RO, CD68, CD163, and FOXP3 immunohistochemistry were evaluated from available archival surgical specimens from primary disease site and neurosurgical resection.

Results

A cohort of 44 patients with BM from gynecologic malignancies was identified, 21 (47.7%) endometrial primaries and 23 (52.3%) ovarian primaries. Tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) were evaluated in 13 primary cases and 15 BM cases. For the 13 primary cases, CD4+ TILs were evident in 76.9% of cases, CD8+ in 92.3%, CD45RO+ in 92.3%, and FOXP3+ in 46.2%, as well as CD68+ TAMs in 100% and CD163+ in 100%. For the 15 BM cases, CD4+ TILs were evident in 60.0% of cases, CD8+ in 93.3%, CD45RO+ in 73.3%, and FOXP3+ in 35.7%, as well as CD68+ TAMs in 86.7% and CD163+ in 100%.

Conclusion

An active tumor immune microenvironment is present with similar distribution in the primary disease site and BM from patients with gynecologic malignancies.

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References

  1. Deng K, Yang C, Tan Q et al (2018) Sites of distant metastases and overall survival in ovarian cancer: a study of 1481 patients. Gynecol Oncol 150:460–465. https://doi.org/10.1016/j.ygyno.2018.06.022

    Article  PubMed  Google Scholar 

  2. Mao W, Wei S, Yang H et al (2020) Clinicopathological study of organ metastasis in endometrial cancer. Future Oncol Lond Engl 16:525–540. https://doi.org/10.2217/fon-2020-0017

    Article  CAS  Google Scholar 

  3. Anupol N, Ghamande S, Odunsi K et al (2002) Evaluation of prognostic factors and treatment modalities in ovarian cancer patients with brain metastases. Gynecol Oncol 85:487–492

    Article  Google Scholar 

  4. Chura JC, Marushin R, Boyd A et al (2007) Multimodal therapy improves survival in patients with CNS metastasis from uterine cancer: a retrospective analysis and literature review. Gynecol Oncol 107:79–85. https://doi.org/10.1016/j.ygyno.2007.05.027

    Article  PubMed  Google Scholar 

  5. Uccella S, Morris JM, Multinu F et al (2016) Primary brain metastases of endometrial cancer: a report of 18 cases and review of the literature. Gynecol Oncol 142:70–75. https://doi.org/10.1016/j.ygyno.2016.04.013

    Article  PubMed  Google Scholar 

  6. Gien LT, Kwon JS, D’Souza DP et al (2004) Brain metastases from endometrial carcinoma: a retrospective study. Gynecol Oncol 93:524–528. https://doi.org/10.1016/j.ygyno.2004.02.006

    Article  PubMed  Google Scholar 

  7. Divine LM, Kizer NT, Hagemann AR et al (2016) Clinicopathologic characteristics and survival of patients with gynecologic malignancies metastatic to the brain. Gynecol Oncol 142:76–82. https://doi.org/10.1016/j.ygyno.2016.04.030

    Article  PubMed  PubMed Central  Google Scholar 

  8. Yano H, Nagao S, Yamaguchi S (2020) Leptomeningeal metastases arising from gynecological cancers. Int J Clin Oncol 25:391–395. https://doi.org/10.1007/s10147-019-01556-1

    Article  PubMed  Google Scholar 

  9. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264. https://doi.org/10.1038/nrc3239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Patel SP, Kurzrock R (2015) PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 14:847–856. https://doi.org/10.1158/1535-7163.MCT-14-0983

    Article  CAS  PubMed  Google Scholar 

  11. Fridman WH, Pagès F, Sautès-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12:298–306. https://doi.org/10.1038/nrc3245

    Article  CAS  PubMed  Google Scholar 

  12. Taube JM, Klein A, Brahmer JR et al (2014) Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 20:5064–5074. https://doi.org/10.1158/1078-0432.CCR-13-3271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lorger M, Andreou T, Fife C, James F (2019) Immune checkpoint blockade—how does it work in brain metastases? Front Mol Neurosci. https://doi.org/10.3389/fnmol.2019.00282

    Article  PubMed  PubMed Central  Google Scholar 

  14. Berghoff AS, Preusser M (2015) The inflammatory microenvironment in brain metastases: potential treatment target? Chin Clin Oncol 4:21. https://doi.org/10.3978/j.issn.2304-3865.2015.06.03

    Article  PubMed  Google Scholar 

  15. Berghoff AS, Ricken G, Widhalm G et al (2015) Tumour-infiltrating lymphocytes and expression of programmed death ligand 1 (PD-L1) in melanoma brain metastases. Histopathology 66:289–299. https://doi.org/10.1111/his.12537

    Article  PubMed  Google Scholar 

  16. Herrera-Rios D, Mughal SS, Teuber-Hanselmann S et al (2020) Macrophages/microglia represent the major source of indolamine 2,3-dioxygenase expression in melanoma metastases of the brain. Front Immunol 11:120. https://doi.org/10.3389/fimmu.2020.00120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kluger HM, Zito CR, Barr ML et al (2015) Characterization of PD-L1 expression and associated T-cell infiltrates in metastatic melanoma samples from variable anatomic sites. Clin Cancer Res Off J Am Assoc Cancer Res 21:3052–3060. https://doi.org/10.1158/1078-0432.CCR-14-3073

    Article  CAS  Google Scholar 

  18. Taggart D, Andreou T, Scott KJ et al (2018) Anti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+ T cell trafficking. Proc Natl Acad Sci U S A 115:E1540–E1549. https://doi.org/10.1073/pnas.1714089115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Batur S, Dulger O, Durak S et al (2019) Concordance of PD-L1 expression and CD8+ TIL intensity between NSCLC and synchronous brain metastases. Bosn J Basic Med Sci. https://doi.org/10.17305/bjbms.2019.4474

    Article  Google Scholar 

  20. Kim R, Keam B, Kim S et al (2019) Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: therapeutic implications for immune checkpoint inhibitors. BMC Cancer 19:19. https://doi.org/10.1186/s12885-018-5214-8

    Article  PubMed  PubMed Central  Google Scholar 

  21. Mansfield AS, Aubry MC, Moser JC et al (2016) Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer. Ann Oncol Off J Eur Soc Med Oncol 27:1953–1958. https://doi.org/10.1093/annonc/mdw289

    Article  CAS  Google Scholar 

  22. Pocha K, Mock A, Rapp C et al (2020) Surfactant expression defines an inflamed subtype of lung adenocarcinoma brain metastases that correlates with prolonged survival. Clin Cancer Res Off J Am Assoc Cancer Res. https://doi.org/10.1158/1078-0432.CCR-19-2184

    Article  Google Scholar 

  23. Téglási V, Pipek O, Lózsa R et al (2019) PD-L1 expression of lung cancer cells, unlike infiltrating immune cells, is stable and unaffected by therapy during brain metastasis. Clin Lung Cancer 20:363-369.e2. https://doi.org/10.1016/j.cllc.2019.05.008

    Article  CAS  PubMed  Google Scholar 

  24. Téglási V, Reiniger L, Fábián K et al (2017) Evaluating the significance of density, localization, and PD-1/PD-L1 immunopositivity of mononuclear cells in the clinical course of lung adenocarcinoma patients with brain metastasis. Neuro-Oncol 19:1058–1067. https://doi.org/10.1093/neuonc/now309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhou J, Gong Z, Jia Q et al (2018) Programmed death ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density differences between paired primary and brain metastatic lesions in non-small cell lung cancer. Biochem Biophys Res Commun 498:751–757. https://doi.org/10.1016/j.bbrc.2018.03.053

    Article  CAS  PubMed  Google Scholar 

  26. Duchnowska R, Pęksa R, Radecka B et al (2016) Immune response in breast cancer brain metastases and their microenvironment: the role of the PD-1/PD-L axis. Breast Cancer Res BCR 18:43. https://doi.org/10.1186/s13058-016-0702-8

    Article  CAS  PubMed  Google Scholar 

  27. Cimino-Mathews A, Ye X, Meeker A et al (2013) Metastatic triple-negative breast cancers at first relapse have fewer tumor-infiltrating lymphocytes than their matched primary breast tumors: a pilot study. Hum Pathol 44:2055–2063. https://doi.org/10.1016/j.humpath.2013.03.010

    Article  PubMed  PubMed Central  Google Scholar 

  28. Lee M, Heo S-H, Song IH et al (2019) Presence of tertiary lymphoid structures determines the level of tumor-infiltrating lymphocytes in primary breast cancer and metastasis. Mod Pathol 32:70–80. https://doi.org/10.1038/s41379-018-0113-8

    Article  CAS  PubMed  Google Scholar 

  29. Liu Y, Komohara Y, Domenick N et al (2012) Expression of antigen processing and presenting molecules in brain metastasis of breast cancer. Cancer Immunol Immunother CII 61:789–801. https://doi.org/10.1007/s00262-011-1137-9

    Article  CAS  PubMed  Google Scholar 

  30. Ogiya R, Niikura N, Kumaki N et al (2017) Comparison of immune microenvironments between primary tumors and brain metastases in patients with breast cancer. Oncotarget 8:103671–103681. https://doi.org/10.18632/oncotarget.22110

    Article  PubMed  PubMed Central  Google Scholar 

  31. Sobottka B, Pestalozzi B, Fink D et al (2016) Similar lymphocytic infiltration pattern in primary breast cancer and their corresponding distant metastases. Oncoimmunology 5:e1153208. https://doi.org/10.1080/2162402X.2016.1153208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhu L, Narloch JL, Onkar S et al (2019) Metastatic breast cancers have reduced immune cell recruitment but harbor increased macrophages relative to their matched primary tumors. J Immunother Cancer 7:265. https://doi.org/10.1186/s40425-019-0755-1

    Article  PubMed  PubMed Central  Google Scholar 

  33. Berghoff AS, Ricken G, Wilhelm D et al (2016) Tumor infiltrating lymphocytes and PD-L1 expression in brain metastases of small cell lung cancer (SCLC). J Neurooncol 130:19–29. https://doi.org/10.1007/s11060-016-2216-8

    Article  CAS  PubMed  Google Scholar 

  34. Roussille P, Tachon G, Villalva C et al (2018) Pathological and molecular characteristics of colorectal cancer with brain metastases. Cancers. https://doi.org/10.3390/cancers10120504

    Article  PubMed  PubMed Central  Google Scholar 

  35. Dahlin AM, Henriksson ML, Van Guelpen B et al (2011) Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor. Mod Pathol 24:671–682. https://doi.org/10.1038/modpathol.2010.234

    Article  CAS  PubMed  Google Scholar 

  36. Pakneshan S, Safarpour D, Tavassoli F, Jabbari B (2014) Brain metastasis from ovarian cancer: a systematic review. J Neurooncol 119:1–6. https://doi.org/10.1007/s11060-014-1447-9

    Article  PubMed  Google Scholar 

  37. Pothuri B, Chi DS, Reid T et al (2002) Craniotomy for central nervous system metastases in epithelial ovarian carcinoma. Gynecol Oncol 87:133–137

    Article  Google Scholar 

  38. Berghoff AS, Fuchs E, Ricken G et al (2016) Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. Oncoimmunology 5:e1057388. https://doi.org/10.1080/2162402X.2015.1057388

    Article  CAS  PubMed  Google Scholar 

  39. Adeegbe DO, Nishikawa H (2013) Natural and induced T regulatory cells in cancer. Front Immunol 4:190. https://doi.org/10.3389/fimmu.2013.00190

    Article  PubMed  PubMed Central  Google Scholar 

  40. Webb JR, Milne K, Kroeger DR, Nelson BH (2016) PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer. Gynecol Oncol 141:293–302. https://doi.org/10.1016/j.ygyno.2016.03.008

    Article  CAS  PubMed  Google Scholar 

  41. Hendry S, Salgado R, Gevaert T et al (2017) Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non-Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors. Adv Anat Pathol 24:311–335. https://doi.org/10.1097/PAP.0000000000000161

    Article  PubMed  PubMed Central  Google Scholar 

  42. Akbay EA, Koyama S, Carretero J et al (2013) Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov 3:1355–1363. https://doi.org/10.1158/2159-8290.CD-13-0310

    Article  CAS  PubMed  Google Scholar 

  43. Brastianos PK, Carter SL, Santagata S et al (2015) Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov 5:1164–1177. https://doi.org/10.1158/2159-8290.CD-15-0369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lee CC, Soon YY, Lum JHY et al (2020) Frequency of discordance in programmed death-ligand 1 (PD-L1) expression between primary tumors and paired distant metastases in advanced cancers: a systematic review and meta-analysis. Acta Oncol. https://doi.org/10.1080/0284186X.2020.1741678

    Article  PubMed  Google Scholar 

  45. Ratner E, Bala M, Louie-Gao M et al (2019) Increased risk of brain metastases in ovarian cancer patients with BRCA mutations. Gynecol Oncol 153:568–573. https://doi.org/10.1016/j.ygyno.2019.03.004

    Article  PubMed  Google Scholar 

  46. Stasenko M, Cybulska P, Feit N et al (2019) Brain metastasis in epithelial ovarian cancer by BRCA1/2 mutation status. Gynecol Oncol 154:144–149. https://doi.org/10.1016/j.ygyno.2019.05.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Balendran S, Liebmann-Reindl S, Berghoff AS et al (2017) Next-Generation Sequencing-based genomic profiling of brain metastases of primary ovarian cancer identifies high number of BRCA-mutations. J Neurooncol 133:469–476. https://doi.org/10.1007/s11060-017-2459-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sekine M, Yoshihara K, Komata D et al (2013) Increased incidence of brain metastases in BRCA1-related ovarian cancers. J Obstet Gynaecol Res 39:292–296. https://doi.org/10.1111/j.1447-0756.2012.01961.x

    Article  CAS  PubMed  Google Scholar 

  49. Colombo I, Garg S, Danesh A et al (2019) Heterogeneous alteration of the ERBB3-MYC axis associated with MEK inhibitor resistance in a KRAS-mutated low-grade serous ovarian cancer patient. Cold Spring Harb Mol Case Stud. https://doi.org/10.1101/mcs.a004341

    Article  PubMed  PubMed Central  Google Scholar 

  50. Bangham M, Goldstein R, Walton H, Ledermann JA (2016) Olaparib treatment for BRCA-mutant ovarian cancer with leptomeningeal disease. Gynecol Oncol Rep 18:22–24. https://doi.org/10.1016/j.gore.2016.10.004

    Article  PubMed  PubMed Central  Google Scholar 

  51. Gray S, Khor XY, Yiannakis D (2019) Niraparib as maintenance therapy in a patient with ovarian cancer and brain metastases. BMJ Case Rep. https://doi.org/10.1136/bcr-2019-230738

    Article  PubMed  PubMed Central  Google Scholar 

  52. Lin NU, Lee EQ, Aoyama H et al (2015) Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol 16:e270-278. https://doi.org/10.1016/S1470-2045(15)70057-4

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank Dana-Farber/Harvard Cancer Center in Boston, MA, for the use of the Specialized Histopathology Core, which provided histology and immunohistochemistry service. Dana-Farber/Harvard Cancer Center is supported in part by an NCI Cancer Center Support Grant # NIH 5 P30 CA06516.

Funding

This study was funded by Department of Obstetrics, Gynecology, and Reproductive Science Innovation Award; Icahn School of Medicine at Mount Sinai.

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Authors and Affiliations

  1. Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA

    Corey M. Gill, Megan R. D’Andrea & Raj K. Shrivastava

  2. Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Shannon Tomita, Jessa Suhner, Konstantin Zakashansky, Stephanie V. Blank & Valentin Kolev

  3. Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Melissa Umphlett, Nadejda Tsankova & Mary Fowkes

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  1. Corey M. Gill
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Contributions

Corey M. Gill contributed to conceptualization, methodology, formal analysis, investigation, data curation, writing—original draft, writing—review and editing, visualization, and funding acquisition; Megan D’Andrea, Shannon Tomita, Jessa Suhner, Melissa Umphlett, and Konstantin Zakashansky contributed to investigation and writing—review and editing; Stephanie Blank, Nadejda Tsankova, and Raj Shrivastava contributed to resources, writing—review and editing, and supervision; Mary Fowkes contributed to conceptualization, methodology, resources, writing—review and editing, and supervision; Valentin Kolev contributed to conceptualization, methodology, resources, writing—original draft, writing—review and editing, supervision, and funding acquisition.

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Correspondence to Corey M. Gill.

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Gill, C.M., D’Andrea, M.R., Tomita, S. et al. Tumor immune microenvironment in brain metastases from gynecologic malignancies. Cancer Immunol Immunother 70, 2951–2960 (2021). https://doi.org/10.1007/s00262-021-02909-4

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