Biologic meshes and synthetic meshes in cancer patients: a double-edged sword: differences in production of IL-6 and IL-12 caused by acellular dermal matrices in human immune cells
In 2005, Breuing et al. first described the use of acellular dermal matrices (ADMs) in breast cancer patients. ADMs are assumed to be safe to use in an oncologic setting, but data from controlled studies are still needed. Here, we investigate the effects of ADMs on the production of interleukin (IL)-6 and IL-12, key regulators of immune suppression and activation.
Strattice (ST), CollaMend (CM), and Biodesign (BD) biologic meshes and TiLoop, a synthetic mesh (TL), were used in this study. We isolated myeloid dendritic cells (MDCs), untouched plasmacytoid dendritic cells (pDCs), naïve B cells, and CD8+ T cells and co-cultured these cells with either the biologic meshes or TL. As positive controls, we used CpG ODN 2216 or lipopolysaccharide (LPS). The cytokine concentrations of IL-12p70 and IL-6 were determined after 7 days using sandwich ELISA sets.
There were highly significant differences between the ADMs and TL in terms of their ability to stimulate immunologic responses. IL-6 expression was significantly increased in B cells (p = 0.0006131) and T cells (p = 0.00418) when comparing TL and ADMs. We also identified significant differences in IL-12 production by B cells (p = 0.0166) and T cells (p = 0.003636) when comparing TL and ADMs.
Despite the assumed lack of an immunological response to ADMs, in our experimental study, human immune cells reacted with significantly different cytokine profiles. These findings may have implications for the potential activation or suppression of effector cells in cancer patients and could explain some of the post clinical post surgical signs of ADMS like skin rush and seroma.
KeywordsAcellular dermal matrices Interleukin-6 Interleukin-12 IL-6 IL-12 Breast cancer
This study was presented in part in poster format at the 2013 Annual Meeting of the American Society of Clinical Oncology, May 31–June 4, Chicago, IL.
MK: conceptualization, data curation, funding acquisition, investigation, project administration, writing original draft, and supervision. SE: investigation, methodology. JK: writing, review, and editing. VK: methodology. PD: investigation. BR: funding acquisition, methodology. JB: writing and review. DM: investigation and conceptualization. DD: conceptualization and supervision.
The study was supported by a Grant from the Klinik für Frauenheilkunde, Ludwig-Maximilians-Universität München, München, Deutschland.
Compliance with ethical standards
Conflict of interest
The authors have no conflicts of interest to declare.
The study was approved by the ethics committee of the Ludwig-Maximilians-Universität München.
All study participants gave written informed consent for this study.
- 1.Badylak SF, Tullius R, Kokini K, Shelbourne KD, Klootwyk T, Voytik SL, Kraine MR, Simmons C (1995) The use of xenogeneic small intestinal submucosa as a biomaterial for Achilles tendon repair in a dog model. J Biomed Mater Res 29:977–985. https://doi.org/10.1002/jbm.820290809 CrossRefPubMedGoogle Scholar
- 3.Bayrak A, Tyralla M, Ladhoff J, Schleicher M, Stock UA, Volk HD, Seifert M (2010) Human immune responses to porcine xenogeneic matrices and their extracellular matrix constituents in vitro. Biomaterials 31:3793–3803. https://doi.org/10.1016/j.biomaterials.2010.01.120 CrossRefPubMedGoogle Scholar
- 5.Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, Loudon R, Sherman F, Perussia B, Trinchieri G (1989) Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med 170:827–845CrossRefPubMedGoogle Scholar
- 6.Stern AS, Podlaski FJ, Hulmes JD, Pan YC, Quinn PM, Wolitzky AG, Familletti PC, Stremlo DL, Truitt T, Chizzonite R et al (1990) Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc Natl Acad Sci USA 87:6808–6812CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Lenzi R, Rosenblum M, Verschraegen C, Kudelka AP, Kavanagh JJ, Hicks ME, Lang EA, Nash MA, Levy LB, Garcia ME, Platsoucas CD, Abbruzzese JL, Freedman RS (2002) Phase I study of intraperitoneal recombinant human interleukin 12 in patients with Mullerian carcinoma, gastrointestinal primary malignancies, and mesothelioma. Clin Cancer Res 8:3686–3695PubMedGoogle Scholar
- 9.Portielje JE, Lamers CH, Kruit WH, Sparreboom A, Bolhuis RL, Stoter G, Huber C, Gratama JW (2003) Repeated administrations of interleukin (IL)-12 are associated with persistently elevated plasma levels of IL-10 and declining IFN-gamma, tumor necrosis factor-alpha, IL-6, and IL-8 responses. Clin Cancer Res 9:76–83PubMedGoogle Scholar
- 10.Haicheur N, Escudier B, Dorval T, Negrier S, De Mulder PH, Dupuy JM, Novick D, Guillot T, Wolf S, Pouillart P, Fridman WH, Tartour E (2000) Cytokines and soluble cytokine receptor induction after IL-12 administration in cancer patients. Clin Exp Immunol 119:28–37CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Broderick L, Yokota SJ, Reineke J, Mathiowitz E, Stewart CC, Barcos M, Kelleher RJ Jr, Bankert RB (2005) Human CD4+ effector memory T cells persisting in the microenvironment of lung cancer xenografts are activated by local delivery of IL-12 to proliferate, produce IFN-gamma, and eradicate tumor cells. J Immunol 174:898–906CrossRefPubMedGoogle Scholar
- 13.Kilinc MO, Aulakh KS, Nair RE, Jones SA, Alard P, Kosiewicz MM, Egilmez NK (2006) Reversing tumor immune suppression with intratumoral IL-12: activation of tumor-associated T effector/memory cells, induction of T suppressor apoptosis, and infiltration of CD8+ T effectors. J Immunol 177:6962–6973CrossRefPubMedGoogle Scholar
- 15.Daud AI, DeConti RC, Andrews S, Urbas P, Riker AI, Sondak VK, Munster PN, Sullivan DM, Ugen KE, Messina JL, Heller R (2008) Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma. J Clin Oncol 26:5896–5903. https://doi.org/10.1200/JCO.2007.15.6794 CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Hirano T, Yasukawa K, Harada H, Taga T, Watanabe Y, Matsuda T, Kashiwamura S, Nakajima K, Koyama K, Iwamatsu A et al (1986) Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 324:73–76. https://doi.org/10.1038/324073a0 CrossRefPubMedGoogle Scholar
- 21.George DJ, Halabi S, Shepard TF, Sanford B, Vogelzang NJ, Small EJ, Kantoff PW (2005) The prognostic significance of plasma interleukin-6 levels in patients with metastatic hormone-refractory prostate cancer: results from cancer and leukemia group B 9480. Clin Cancer Res 11:1815–1820. https://doi.org/10.1158/1078-0432.CCR-04-1560 CrossRefPubMedGoogle Scholar
- 22.Alexandrakis MG, Passam FH, Kyriakou DS, Dambaki C, Katrinakis G, Tsirakis G, Konsolas J, Stathopoulos EN (2004) Expression of the proliferation-associated nuclear protein MIB-1 and its relationship with microvascular density in bone marrow biopsies of patients with myelodysplastic syndromes. J Mol Histol 35:857–863. https://doi.org/10.1007/s10735-004-2341-0 CrossRefPubMedGoogle Scholar
- 25.Wong AK, Schonmeyr B, Singh P, Carlson DL, Li S, Mehrara BJ (2008) Histologic analysis of angiogenesis and lymphangiogenesis in acellular human dermis. Plast Reconstr Surg 121:1144–1152. https://doi.org/10.1097/01.prs.0000302505.43942.07 CrossRefPubMedGoogle Scholar
- 27.Dieterich M, Stubert J, Gerber B, Reimer T, Richter DU (2015) Biocompatibility, cell growth and clinical relevance of synthetic meshes and biological matrixes for internal support in implant-based breast reconstruction. Arch Gynecol Obstet 291:1371–1379. https://doi.org/10.1007/s00404-014-3578-9 CrossRefPubMedGoogle Scholar
- 28.Dieterich M, Paepke S, Zwiefel K, Dieterich H, Blohmer J, Faridi A, Klein E, Gerber B, Nestle-Kraemling C (2013) Implant-based breast reconstruction using a titanium-coated polypropylene mesh (TiLOOP Bra): a multicenter study of 231 cases. Plast Reconstr Surg 132:8e–19e. https://doi.org/10.1097/PRS.0b013e318290f8a0 CrossRefPubMedGoogle Scholar
- 32.Younes A, Pro B, Robertson MJ, Flinn IW, Romaguera JE, Hagemeister F, Dang NH, Fiumara P, Loyer EM, Cabanillas FF, McLaughlin PW, Rodriguez MA, Samaniego F (2004) Phase II clinical trial of interleukin-12 in patients with relapsed and refractory non-Hodgkin’s lymphoma and Hodgkin’s disease. Clin Cancer Res 10:5432–5438. https://doi.org/10.1158/1078-0432.CCR-04-0540 CrossRefPubMedGoogle Scholar
- 33.Castellani ML, Anogeianaki A, Felaco P, Toniato E, De Lutiis MA, Shaik B, Fulcheri M, Vecchiet J, Tete S, Salini V, Theoharides TC, Caraffa A, Antinolfi P, Frydas I, Conti P, Cuccurullo C, Ciampoli C, Cerulli G, Kempuraj D (2010) IL-35, an anti-inflammatory cytokine which expands CD4+ CD25+ Treg cells. J Biol Regul Homeost Agents 24:131–135PubMedGoogle Scholar