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The effect of the peritoneal tumor microenvironment on invasion of peritoneal metastases of high-grade serous ovarian cancer and the impact of NEOADJUVANT chemotherapy

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Abstract

Peritoneal metastases of high-grade serous ovarian cancer (HGSOC) are small-sized deposits with superficial growth toward the peritoneal cavity. It is unknown whether integrity of the peritoneal elastic lamina (PEL) correlates with the peritoneal tumor microenvironment (pTME) and whether neoadjuvant chemotherapy (NACT) affects the pTME. We explored integrity of PEL, composition of pTME, effects of NACT, and the prognostic implications in patients with extensive peritoneal metastases of HGSOC. Peritoneal samples (n = 69) were collected during cytoreductive surgery between 2003 and 2016. Clinical data were collected from medical charts. Integrity of PEL was evaluated with elastic stains. T cell (CD3, CD8) and M2-macrophage markers (CD163) were scored using algorithms created in definiens tissue studio. Patients with a disrupted PEL (n = 39; 57%), more often had residual disease after surgery (p = 0.050), compared to intact PEL. An intact PEL was associated with increased intraepithelial (ie) CD8+ cells (p = 0.032), but was not correlated with improved survival. After NACT, increased ieCD3+ cells were shown, compared to no-NACT (p = 0.044). Abundance of total CD3+ and CD8+ cells were associated with PFS (multivariate HR 0.40; 95%CI 0.23–0.69 and HR 0.49; 95%CI 0.29–0.83) and OS (HR 0.33; 95%CI 0.18–0.62 and HR 0.36; 95%CI 0.20–0.64). M2-macrophage infiltration was not correlated with survival. NACT increases abundance of ieCD3+ cells in peritoneal metastases of HGSOC. Increase of CD3+ and CD8+ cells is associated with improved PFS and OS. This suggests that CD3+ and CD8+ cells may function as prognostic biomarkers. Their role as predictive biomarker for chemotherapy or immunotherapy response in HGSOC warrants further research.

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  • 02 December 2020

    A correction to this paper has been published: <ExternalRef><RefSource>https://doi.org/10.1007/s00428-020-02974-7</RefSource><RefTarget Address="10.1007/s00428-020-02974-7" TargetType="DOI"/></ExternalRef>

References

  1. van Baal JO, Van de Vijver KK, Nieuwland R, van Noorden CJ et al (2017) The histophysiology and pathophysiology of the peritoneum. Tissue Cell 49(1):95–105. https://doi.org/10.1016/j.tice.2016.11.004

    Article  PubMed  Google Scholar 

  2. Knudsen PJ (1991) The peritoneal elastic lamina. J Anat 177:41–46

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Yokota M, Kojima M, Nomura S, Nishizawa Y, Kobayashi A, Ito M, Ochiai A, Saito N (2014) Clinical impact of elastic laminal invasion in colon cancer: elastic laminal invasion-positive stage II colon cancer is a high-risk equivalent to stage III. Dis Colon Rectum 57(7):830–838. https://doi.org/10.1097/DCR.0000000000000124

    Article  PubMed  Google Scholar 

  4. Shinto E, Ueno H, Hashiguchi Y, Hase K, Tsuda H, Matsubara O, Mochizuki H (2004) The subserosal elastic lamina: an anatomic landmark for stratifying pT3 colorectal cancer. Dis Colon Rectum 47(4):467–473. https://doi.org/10.1007/s10350-003-0083-9

    Article  PubMed  Google Scholar 

  5. Leinster DA, Kulbe H, Everitt G, Thompson R, Perretti M, Gavins FN, Cooper D, Gould D, Ennis DP, Lockley M, McNeish I, Nourshargh S, Balkwill FR (2012) The peritoneal tumour microenvironment of high-grade serous ovarian cancer. J Pathol 227(2):136–145. https://doi.org/10.1002/path.4002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348(3):203–213. https://doi.org/10.1056/NEJMoa020177

    Article  CAS  PubMed  Google Scholar 

  7. Clarke B, Tinker AV, Lee CH, Subramanian S, van de Rijn M, Turbin D, Kalloger S, Han G, Ceballos K, Cadungog MG, Huntsman DG, Coukos G, Gilks CB (2009) Intraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 loss. Mod Pathol 22(3):393–402. https://doi.org/10.1038/modpathol.2008.191

    Article  CAS  PubMed  Google Scholar 

  8. Milne K, Kobel M, Kalloger SE, Barnes RO et al (2009) Systematic analysis of immune infiltrates in high-grade serous ovarian cancer reveals CD20, FoxP3 and TIA-1 as positive prognostic factors. PLoS One 4(7):e6412. https://doi.org/10.1371/journal.pone.0006412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lan C, Huang X, Lin S, Huang H, Cai Q, Wan T, Lu J, Liu J (2013) Expression of M2-polarized macrophages is associated with poor prognosis for advanced epithelial ovarian cancer. Technol Cancer Res Treat 12(3):259–267. https://doi.org/10.7785/tcrt.2012.500312

    Article  CAS  PubMed  Google Scholar 

  10. Reinartz S, Schumann T, Finkernagel F, Wortmann A, Jansen JM, Meissner W, Krause M, Schwörer AM, Wagner U, Müller-Brüsselbach S, Müller R (2014) Mixed-polarization phenotype of ascites-associated macrophages in human ovarian carcinoma: correlation of CD163 expression, cytokine levels and early relapse. Int J Cancer 134(1):32–42. https://doi.org/10.1002/ijc.28335

    Article  CAS  PubMed  Google Scholar 

  11. Hendry S, Salgado R, Gevaert T, Russell PA 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(6):311–335. https://doi.org/10.1097/PAP.0000000000000161

    Article  PubMed  PubMed Central  Google Scholar 

  12. Hendry S, Salgado R, Gevaert T, Russell PA, John T, Thapa B, Christie M, van de Vijver K, Estrada MV, Gonzalez-Ericsson PI, Sanders M, Solomon B, Solinas C, van den Eynden G, Allory Y, Preusser M, Hainfellner J, Pruneri G, Vingiani A, Demaria S, Symmans F, Nuciforo P, Comerma L, Thompson EA, Lakhani S, Kim SR, Schnitt S, Colpaert C, Sotiriou C, Scherer SJ, Ignatiadis M, Badve S, Pierce RH, Viale G, Sirtaine N, Penault-Llorca F, Sugie T, Fineberg S, Paik S, Srinivasan A, Richardson A, Wang Y, Chmielik E, Brock J, Johnson DB, Balko J, Wienert S, Bossuyt V, Michiels S, Ternes N, Burchardi N, Luen SJ, Savas P, Klauschen F, Watson PH, Nelson BH, Criscitiello C, O'Toole S, Larsimont D, de Wind R, Curigliano G, André F, Lacroix-Triki M, van de Vijver M, Rojo F, Floris G, Bedri S, Sparano J, Rimm D, Nielsen T, Kos Z, Hewitt S, Singh B, Farshid G, Loibl S, Allison KH, Tung N, Adams S, Willard-Gallo K, Horlings HM, Gandhi L, Moreira A, Hirsch F, Dieci MV, Urbanowicz M, Brcic I, Korski K, Gaire F, Koeppen H, Lo A, Giltnane J, Rebelatto MC, Steele KE, Zha J, Emancipator K, Juco JW, Denkert C, Reis-Filho J, Loi S, Fox SB (2017) Assessing tumor-infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the international Immunooncology biomarkers working group: part 1: assessing the host immune response, TILs in invasive breast carcinoma and ductal carcinoma in situ, metastatic tumor deposits and areas for further research. Adv Anat Pathol 24(5):235–251. https://doi.org/10.1097/PAP.0000000000000162

    Article  PubMed  PubMed Central  Google Scholar 

  13. Rustin GJ, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, du Bois A, Kristensen G, Jakobsen A, Sagae S, Greven K, Parmar M, Friedlander M, Cervantes A, Vermorken J, Gynecological Cancer Intergroup (2011) Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the gynecological Cancer intergroup (GCIG). Int J Gynecol Cancer 21(2):419–423. https://doi.org/10.1097/IGC.0b013e3182070f17

    Article  PubMed  Google Scholar 

  14. Manning-Geist BL, Hicks-Courant K, Gockley AA, Clark RM, del Carmen M, Growdon WB, Horowitz NS, Berkowitz RS, Muto MG, Worley MJ Jr (2018) Moving beyond "complete surgical resection" and "optimal": is low-volume residual disease another option for primary debulking surgery? Gynecol Oncol 150(2):233–238. https://doi.org/10.1016/j.ygyno.2018.06.015

    Article  PubMed  Google Scholar 

  15. Chi DS, Eisenhauer EL, Lang J, Huh J, Haddad L, Abu-Rustum NR, Sonoda Y, Levine DA, Hensley M, Barakat RR (2006) What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)? Gynecol Oncol 103(2):559–564. https://doi.org/10.1016/j.ygyno.2006.03.051

    Article  CAS  PubMed  Google Scholar 

  16. Chang SJ, Hodeib M, Chang J, Bristow RE (2013) Survival impact of complete cytoreduction to no gross residual disease for advanced-stage ovarian cancer: a meta-analysis. Gynecol Oncol 130(3):493–498. https://doi.org/10.1016/j.ygyno.2013.05.040

    Article  PubMed  Google Scholar 

  17. Grin A, Messenger DE, Cook M, O'Connor BI, Hafezi S, el-Zimaity H, Kirsch R (2013) Peritoneal elastic lamina invasion: limitations in its use as a prognostic marker in stage II colorectal cancer. Hum Pathol 44(12):2696–2705. https://doi.org/10.1016/j.humpath.2013.07.013

    Article  CAS  PubMed  Google Scholar 

  18. Kojima M, Nakajima K, Ishii G, Saito N, Ochiai A (2010) Peritoneal elastic laminal invasion of colorectal cancer: the diagnostic utility and clinicopathologic relationship. Am J Surg Pathol 34(9):1351–1360. https://doi.org/10.1097/PAS.0b013e3181ecfe98

    Article  PubMed  Google Scholar 

  19. Liang WY, Chang WC, Hsu CY, Arnason T, Berger D, Hawkins AT, Sylla P, Lauwers GY (2013) Retrospective evaluation of elastic stain in the assessment of serosal invasion of pT3N0 colorectal cancers. Am J Surg Pathol 37(10):1565–1570. https://doi.org/10.1097/PAS.0b013e31828ea2de

    Article  PubMed  Google Scholar 

  20. Liang WY, Wang YC, Hsu CY, Yang SH (2018) Staging of colorectal cancers based on elastic Lamina invasion. Hum Pathol. https://doi.org/10.1016/j.humpath.2018.10.019

  21. Lu J, Hu X, Meng Y, Zhao H, Cao Q, Jin M (2018) The prognosis significance and application value of peritoneal elastic lamina invasion in colon cancer. PLoS One 13(4):e0194804. https://doi.org/10.1371/journal.pone.0194804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331(6024):1565–1570. https://doi.org/10.1126/science.1203486

    Article  CAS  PubMed  Google Scholar 

  23. Fridman WH, Pages F, Sautes-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12(4):298–306. https://doi.org/10.1038/nrc3245

    Article  CAS  PubMed  Google Scholar 

  24. Li J, Wang J, Chen R, Bai Y et al (2017) The prognostic value of tumor-infiltrating T lymphocytes in ovarian cancer. Oncotarget 8(9):15621–15631. https://doi.org/10.18632/oncotarget.14919

    Article  PubMed  PubMed Central  Google Scholar 

  25. Mesnage SJL, Auguste A, Genestie C, Dunant A, Pain E, Drusch F, Gouy S, Morice P, Bentivegna E, Lhomme C, Pautier P, Michels J, le Formal A, Cheaib B, Adam J, Leary AF (2017) Neoadjuvant chemotherapy (NACT) increases immune infiltration and programmed death-ligand 1 (PD-L1) expression in epithelial ovarian cancer (EOC). Ann Oncol 28(3):651–657. https://doi.org/10.1093/annonc/mdw625

    Article  CAS  PubMed  Google Scholar 

  26. Lo CS, Sanii S, Kroeger DR, Milne K, Talhouk A, Chiu DS, Rahimi K, Shaw PA, Clarke BA, Nelson BH (2017) Neoadjuvant chemotherapy of ovarian Cancer results in three patterns of tumor-infiltrating lymphocyte response with distinct implications for immunotherapy. Clin Cancer Res 23(4):925–934. https://doi.org/10.1158/1078-0432.CCR-16-1433

    Article  CAS  PubMed  Google Scholar 

  27. Bohm S, Montfort A, Pearce OM, Topping J et al (2016) Neoadjuvant chemotherapy modulates the immune microenvironment in metastases of Tubo-ovarian high-grade serous carcinoma. Clin Cancer Res 22(12):3025–3036. https://doi.org/10.1158/1078-0432.CCR-15-2657

    Article  CAS  PubMed  Google Scholar 

  28. Polcher M, Braun M, Friedrichs N, Rudlowski C et al (2010) Foxp3(+) cell infiltration and granzyme B(+)/Foxp3(+) cell ratio are associated with outcome in neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer Immunol Immunother 59(6):909–919. https://doi.org/10.1007/s00262-010-0817-1

    Article  CAS  PubMed  Google Scholar 

  29. Peng J, Hamanishi J, Matsumura N, Abiko K, Murat K, Baba T, Yamaguchi K, Horikawa N, Hosoe Y, Murphy SK, Konishi I, Mandai M (2015) Chemotherapy induces programmed cell death-ligand 1 overexpression via the nuclear factor-kappaB to Foster an immunosuppressive tumor microenvironment in ovarian Cancer. Cancer Res 75(23):5034–5045. https://doi.org/10.1158/0008-5472.CAN-14-3098

    Article  CAS  Google Scholar 

  30. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528):568–571. https://doi.org/10.1038/nature13954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Vayrynen JP, Vornanen JO, Sajanti S, Bohm JP et al (2012) An improved image analysis method for cell counting lends credibility to the prognostic significance of T cells in colorectal cancer. Virchows Arch 460(5):455–465. https://doi.org/10.1007/s00428-012-1232-0

    Article  CAS  PubMed  Google Scholar 

  32. Pages F, Berger A, Camus M, Sanchez-Cabo F et al (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353(25):2654–2666. https://doi.org/10.1056/NEJMoa051424

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We would like to acknowledge the NKI-AVL Core Facility Molecular Pathology & Biobanking for supplying NKI-AVL Biobank material and lab support.

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Authors and Affiliations

  1. Department of Gynecology, Center for Gynecologic Oncology Amsterdam, P.O. Box 90203, Amsterdam, 1006, BE, The Netherlands

    J. O. A. M. van Baal, C. A. R. Lok, E. S. Jordanova, W. J. van Driel & F. C. Amant

  2. Division of Diagnostic Oncology & Molecular Pathology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

    H. Horlings & K. K. Van de Vijver

  3. Department of Pathology, Ghent University Hospital, Cancer Research Institute Ghent (CRIG), Ghent, Belgium

    K. K. Van de Vijver

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  1. J. O. A. M. van Baal
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Contributions

All authors contributed to research goals and study design. JB, HH and KV performed histopathological revision and immune scoring of samples. JB and EJ performed digital imaging analyses. JB, EJ, HH and KV contributed to interpretation of data. Acquisition of data, analyses and writing first draft of the paper was performed by JB and CL. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to J. O. A. M. van Baal.

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The present study was approved by the Institutional Review Board of the NKI-AVL (PTC15.0324/M14BBB).

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All authors declare that they have no conflict of interest.

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ESM 1

Kaplan-Meier survival estimate curve demonstrating OS of patients with an intact PEL and patients with a disrupted PEL. Events of death between tumors with an intact PEL (n = 21; 70.0%) and tumors with a disrupted PEL (n = 33; 84.6%; p = 0.238) were similar. Patients with an intact PEL showed a median OS of 31.7 months (95%CI 17.3–46.0), compared with 28.0 months (95%CI 20.7–35.3; Log Rank 1.683; p = 0.195) for patients with a disrupted PEL. After stratification for high density of ieCD8+ cells, OS was similar between patients with an intact PEL (31.3 months; 95%CI 28.9–33.6) and patients with a disrupted PEL (32.6 months; 95%CI 18.6–46.5; Log Rank 0.055; p = 0.814) (PNG 31 kb)

ESM 2

Kaplan-Meier survival estimate curves for OS depicting differences between immune cell populations. Kaplan-Meier survival curves for OS showed a significant improved survival of all patients with high densities of intraepithelial, stromal and total CD3+ and CD8+ cells compared to low densities. Patients with high density ieCD3+ cells showed median OS of 39.9 months (95%CI 9.8–69.9) compared to 27.3 months (95%CI 18.5–36.1) in patients with low density ieCD3+ cells. Patients with high sCD3+ cells showed an OS of 41.4 months (95%CI 15.2–67.5) compared with 27.3 months (95%CI 19.0–35.7) in those with low density sCD3+ cells. High total CD3+ cells corresponded with an OS of 41.4 months (95%CI 14.2–68.6) compared with 27.3 months (95%CI 18.0–36.7) for low density total CD3+ cells. Patients with high ieCD8+ cells showed an OS of 32.6 months (95%CI 23.3–41.9) compared with 24.1 months (95%CI 13.6–34.6) in patients with low density ieCD8+ cells. Patients with high sCD8+ cells demonstrated an OS of 41.4 months (15.3–67.5) compared with 21.1 months (13.2–29.0) for patients with low sCD8+ cells. High total CD8+ cells corresponded with an OS of 38.1 months (24.9–51.3) compared to 21.1 months (11.4–30.8) for low density total CD8+ cells. No survival differences were observed in patients with different numbers of CD163+ cells in the peritoneal metastases. (PNG 170 kb)

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van Baal, J.O.A.M., Lok, C.A.R., Jordanova, E.S. et al. The effect of the peritoneal tumor microenvironment on invasion of peritoneal metastases of high-grade serous ovarian cancer and the impact of NEOADJUVANT chemotherapy. Virchows Arch 477, 535–544 (2020). https://doi.org/10.1007/s00428-020-02795-8

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