CLINICAL IMMUNOLOGY
The immunohistochemical analysis of membrane-bound CD55, CD59 and fluid-phase FH and FH-like complement inhibitors in cancers of ovary and corpus uteri origin
More details
Hide details
Submission date: 2015-03-02
Final revision date: 2015-04-18
Acceptance date: 2015-05-15
Publication date: 2015-10-15
Cent Eur J Immunol 2015;40(3):349-353
KEYWORDS
ABSTRACT
One of the potential therapeutic methods of cancer treatment is the immunotherapy with monoclonal antibodies. This kind of therapy, although devoid of serious side effects, has often insufficient efficacy. The presence of complement inhibitors on the cancer cells, which are able to inactivate complement-mediated immune response represents one of the main reasons for the inefficiency of such therapy. In our studies we investigated the expression of main membrane–bound and fluid-phase complement regulators: CD55, CD59 and factor H/factor H-like in tumour samples of ovarian and corpus uteri cancer. Tissue samples were collected from 50 patients and stained immunohistochemically, with the use of peroxidase-based immunodetection system. Immunohistochemical analysis revealed that complement inhibitors are present in examined tumors although their presence is heterogenous. The most prevalent is the presence of factor H/H-like, localized mostly in tumor stroma and within vascular structures. Membrane bound complement inhibitors are less prominently expressed by cancer cells. CD55 was detected in low percentage of cells, predominantly within cancer tubules. CD59 immunoreactivity was more prevalent in cancer cells, and was localized particularly at the margin of cancer cell tubules. Our results demonstrate that the most prominent complement inhibitor in cancer of ovary and corpus uteri origin is factor H/factor H-like. Blocking or downregulation of this inhibitor should be taken into consideration with regards to improving the efficiency of immunotherapy with monoclonal antibodies.
REFERENCES (29)
1.
Jemal A, Bray F, Center MM, et al. (2011): Global cancer statistics. CA Cancer J Clin 61: 69-90.
2.
Robak T (2014): Current and emerging monoclonal antibody treatments for chronic lymphocytic leukemia: state of the art. Expert Rev Hematol: 1-17.
3.
Nicholson-Weller A, Burge J, Fearon DT, et al. (1982): Isolation of a human erythrocyte membrane glycoprotein with decay-accelerating activity for C3 convertases of the complement system. J Immunol 129: 184-189.
4.
Medof ME, Walter EI, Rutgers JL, et al. (1987): Identification of the complement decay-accelerating factor (DAF) on epithelium and glandular cells and in body fluids. J Exp Med 165: 848-864.
5.
Brodbeck WG, Liu D, Sperry J, et al. (1996): Localization of classical and alternative pathway regulatory activity within the decay-accelerating factor. J Immunol 156: 2528-2533.
6.
Li L, Spendlove I, Morgan J, et al. (2001): CD55 is over-expressed in the tumour environment. Br J Cancer 84: 80-86.
7.
Durrant LG, Chapman MA, Buckley DJ, et al. (2003): Enhanced expression of the complement regulatory protein CD55 predicts a poor prognosis in colorectal cancer patients. Cancer Immunol Immunother 52: 638-642.
8.
Stefanova I, Hilgert I, Kristofova H, et al. (1989): Characterization of a broadly expressed human leucocyte surface antigen MEM-43 anchored in membrane through phosphatidylinositol. Mol Immunol 26: 153-161.
9.
Meri S, Morgan BP, Davies A, et al. (1990): Human protectin (CD59), an 18,000-20,000 MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers. Immunology 71: 1-9.
10.
Rollins SA, Sims PJ (1990): The complement-inhibitory activity of CD59 resides in its capacity to block incorporation of C9 into membrane C5b-9. J Immunol 144: 3478-3483.
11.
Shang Y, Chai N, Gu Y, et al. (2014): Systematic immunohistochemical analysis of the expression of CD46, CD55, and CD59 in colon cancer. Arch Pathol Lab Med 138: 910-919.
12.
Kesselring R, Thiel A, Pries R, et al. (2014): The complement receptors CD46, CD55 and CD59 are regulated by the tumour microenvironment of head and neck cancer to facilitate escape of complement attack. Eur J Cancer 50: 2152-2161.
13.
Madjd Z, Pinder SE, Paish C, et al. (2003): Loss of CD59 expression in breast tumours correlates with poor survival. J Pathol 200: 633-639.
14.
Pangburn MK, Schreiber RD, Muller-Eberhard HJ (1977): Human complement C3b inactivator: isolation, characterization, and demonstration of an absolute requirement for the serum protein beta1H for cleavage of C3b and C4b in solution. J Exp Med 146: 257-270.
15.
Pangburn MK (2000): Host recognition and target differentiation by factor H, a regulator of the alternative pathway of complement. Immunopharmacology 49: 149-157.
16.
Kristensen T, Tack BF (1986): Murine protein H is comprised of 20 repeating units, 61 amino acids in length. Proc Natl Acad Sci U S A 83: 3963-3967.
17.
Zipfel PF, Skerka C (1999): FHL-1/reconectin: a human complement and immune regulator with cell-adhesive function. Immunol Today 20: 135-140.
18.
Junnikkala S, Jokiranta TS, Friese MA, et al. (2000): Exceptional resistance of human H2 glioblastoma cells to complement-mediated killing by expression and utilization of factor H and factor H-like protein 1. J Immunol 164: 6075-6081.
19.
Mostafa AA, Morris DG (2014): Immunotherapy for Lung Cancer: Has it Finally Arrived? Front Oncol 4: 288.
20.
Tse BW, Jovanovic L, Nelson CC, et al. (2014): From Bench to Bedside: Immunotherapy for Prostate Cancer. Biomed Res Int 2014: 981434.
21.
Bjorge L, Hakulinen J, Wahlstrom T, et al. (1997): Complement-regulatory proteins in ovarian malignancies. Int J Cancer 70: 14-25.
22.
Donin N, Jurianz K, Ziporen L, et al. (2003): Complement resistance of human carcinoma cells depends on membrane regulatory proteins, protein kinases and sialic acid. Clin Exp Immunol 131: 254-263.
23.
Mamidi S, Cinci M, Hasmann M, et al. (2013): Lipoplex mediated silencing of membrane regulators (CD46, CD55 and CD59) enhances complement-dependent anti-tumor activity of trastuzumab and pertuzumab. Mol Oncol 7: 580-594.
24.
Junnikkala S, Hakulinen J, Jarva H, et al. (2002): Secretion of soluble complement inhibitors factor H and factor H-like protein (FHL-1) by ovarian tumour cells. Br J Cancer 87: 1119-1127.
25.
Murray KP, Mathure S, Kaul R, et al. (2000): Expression of complement regulatory proteins-CD 35, CD 46, CD 55, and CD 59-in benign and malignant endometrial tissue. Gynecol Oncol 76: 176-182.
26.
Bellone S, Roque D, Cocco E, et al. (2012): Downregulation of membrane complement inhibitors CD55 and CD59 by siRNA sensitises uterine serous carcinoma overexpressing Her2/neu to complement and antibody-dependent cell cytotoxicity in vitro: implications for trastuzumab-based immunotherapy. Br J Cancer 106: 1543-1550.
27.
Nelson D, Fisher S, Robinson B (2014): The “Trojan Horse” approach to tumor immunotherapy: targeting the tumor microenvironment. J Immunol Res 2014: 789069.
28.
Fang H, Declerck YA (2013): Targeting the tumor microenvironment: from understanding pathways to effective clinical trials. Cancer Res 73: 4965-4977.
29.
Lunardi S, Muschel RJ, Brunner TB (2014): The stromal compartments in pancreatic cancer: are there any therapeutic targets? Cancer Lett 343: 147-155.