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Differential Effects of Recombinant Human Leukocyte Interferons on Cell Surface Antigen Expression John W

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Differential Effects of Recombinant Human Leukocyte Interferons on Cell Surface Antigen Expression John W [CANCER RESEARCH 46, 4984-4990, October 1986] Differential Effects of Recombinant Human Leukocyte Interferons on Cell Surface Antigen Expression John W. Greiner,1Paul B. Fisher, Sidney Pestka, and Jeffrey Schlom Laboratory of Tumor Immunology and Biology, NJH/National Cancer Institute, Bethesda, Maryland 20892 [J. W. G., J. SJ; Department of Microbiology, Comprehensive Cancer Center/Institute of Cancer Research, Columbia University, College of Physicians and Surgeons, New York, New York 10032 [P. B. F.]; and Roche Institute of Molecular Biology, Nutley, New Jersey 07110 fS. P.] ABSTRACT interferons, several studies have found significant differences with respect to their biological actions. Interferons are generally Human leukocyte (a) interferon (IFN-a) is composed of a multigene regarded as having antiviral, antiproliferative, differentiation- family within which at least eight different species have been expressed modulatory, and immunomodulatory activities. Studies have in Escherichia coli, isolated, and shown to exert a wide range of biological activities on different human target cells. In this study we utilized eight shown substantial quantitative differences among these species species of IFN-a (A, B, C, D, F, I, J, and K) and investigated then- of recombinant leukocyte interferon in their varied biological respective capabilities to alter the proliferation of a human breast carci and biochemical effects on a range of target cells (9-17). Other noma cell line (MCF-7). The antigens studied were all constitutively studies have demonstrated that the individual species of leu expressed on the MCF-7 cell surface: the M, 180,000 carcinoembryonic kocyte interferon can elicit different antigrowth effects on the antigen; a high molecular weight (>10*) glycoprotein, termed tumor- same target cell (9, 11, 15, 16-19). It was also shown that a associated glycoprotein 72; and a major HLA histocompatibility antigen. single leukocyte interferon species was an effective antiviral The level of expression of each antigen was measured by the binding of agent yet was completely inactive in boosting human natural monoclonal antibodies HI.I, B72J, and W6/32, respectively. A high killer activity (10). Therefore, as originally observed with the degree of diversity was found among the various IFN-a species with respect to their ability to enhance antigen expression and inhibit MCF-7 various natural leukocyte interferon species (15) there seem to cell growth. The two most potent species, IFN-aA and IFN-aB, were exist quantitative and qualitative differences with respect to found to increase the expression of tumor antigens as well as the HLA their abilities to regulate a variety of biological properties of determinant by 2-5-fold. In contrast, IFN-aD and IIV«.) were virtually target cells. inactive in altering antigen expression but did inhibit the growth of MCF- Considerable attention has been focused on the ability of the 7 cells. The remaining IFN-a species, -«('.-<»!•',-a!,and -aK, exerted an interferons to modulate surface antigens on a variety of human intermediate range of activities for both antigen enhancement and inhi cells (reviewed in Ref. 18). Partially purified as well as recom bition of MCF-7 cell growth. The relative ability of each species of 11N- binant leukocyte interferon can enhance the expression of class a to inhibit MCF-7 cell growth appeared to be independent of their I histocompatibility antigens on both normal and transformed effectiveness in augmenting antigen expression. IFN-aD and IFN-oJ, human cells (18, 20-26). Our laboratories have reported that the two species that failed to alter tumor antigen expression, did, however, IFN-aA can increase the binding of MAbs to the surface of seem to interact with the interferon receptor since they inhibited MCF-7 cell growth and competed with other IFN-a species for the increase in human breast and colon carcinoma cells (27, 28). We have carcinoembryonic antigen, tumor-associated glycoprotein 72, or HLA shown that such an increase is a result of the enhanced expres expression. A comparison of the concentrations of each IFN-a necessary sion of tumor antigens, such as the M, 180,000 CEA and the high molecular weight (>106) mucin, TAG-72, which react with to enhance antigen expression revealed that the surface HLA determinant was approximately 10-fold more sensitive to enhancement than was the MAbs B1.1 and B72.3, respectively (18, 24, 26). The anti-CEA tumor antigen, carcinoembryonic antigen. The individual members of the and TAG-72 MAbs are currently being used in several areas in IFN-a family thus differ extensively in their ability to alter the level of the management of human cancers, including (a) serum assays antigen expression on the surface of MCF-7 breast carcinoma cells. The for the detection of antigen; (/>) immunohistochemical assays differential response of these cells to the IFN-a species, which share a for the detection of occult tumor cells in pleural effusions, high degree of sequence homology and bind to the same cell membrane ascites, and fine needle aspirate biopies (29-31); and (c) the receptor, suggest that these biologically related compounds may differ in detection of in situ occult tumors by radio labe led MAbs (32, the biochemical and molecular signals induced distal to binding to the surface interferon receptor. 33). The use of recombinant interferon to augment tumor antigen expression and thereby enhance detection by MAbs for diagnosis and treatment in each of the above situations merit INTRODUCTION consideration. The present study was carried out to evaluate Human IFN-a2 consists of a family of individual species with the different species of IFN-a for their abilities to alter cell proliferation and modulate the level of cell surface antigen amino acid residues that have been shown to differ by as much expression. The antigens monitored were the M, 180,000 CEA, as 20% (1-8). At least eight different species of leukocyte a high molecular weight (>106) mucin termed TAG-72, and interferons have been expressed in Escherichia coli and purified HLA, all of which are constitutively expressed by the human and their biological activities have been compared (6, 9, 10). breast carcinoma cell line, MCF-7. The levels of expression of Besides the difference in amino acid composition of these these antigens were measured by the binding of MAbs Bl.l, Received 4/10/86; revised 6/27/86; accepted 7/1/86. B72.3, and W6/32, respectively (Table 1). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1To whom requests for reprints should be addressed, at Laboratory of Tumor MATERIALS AND METHODS Immunology and Biology, NIH/NCI, Bldg. 10, Room 8B07, Bethesda, MD 20892. Recombinant Human Leukocyte Interferons. The isolation, expres 'The abbreviations used are: IFN-a, (alpha) interferon; MAI»,monoclonal sion, and purification of eight different clones of human leukocyte antibodies; CEA, carcinoembryonic antigen; TAG-72, tumor-associated glycopro interferon have been described (2, 5-7, 11). The interferons were tein 72; USA, bovine serum albumin; RIA, radioimmunoassay; Ali,,,, molar concentration or molecules per cell required to induce a 50% increase in HLA or prepared and purified as described (8, 9, 11, 34). Unless otherwise tumor antigen expression. noted, the specific activity of the preparations on MDBK cells was 1- 4984 Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1986 American Association for Cancer Research. DIVERSITY AMONG HUMAN IFN-as FOR ANTIGEN AUGMENTATION 5 x 10s antiviral units/mg protein with respect to the human IFN-a M!of 2 N NaOH and the amount of monoclonal antibody bound to the reference standard. Preparations with specific activities ^\ x IO8units/ cell surface (i.e., I25l-labeled radioactivity) was determined in a gamma ml were at least 90% homogeneous as determined by sodium dodecyl counter. Control MCF-7 cells received either a control MAb, the mouse sulfate-polyacrylamide gel electrophoresis (34). IFN-aB represented myeloma IgG (termed MOPC-21), or RPMI 1640 containing 1% BSA. about 75% of the total protein. IFN-aF was a crude bacterial extract. The background radioactivity (<300 cpm/well) was subtracted from The interferons were diluted with RPMI 1640 containing 25 mM 4-(2- the wells that received the monoclonal antibodies of interest. Finally, hydroxyethyl)-l-piperazineethenesulfonic acid and 1% bovine serum cells from 6-10 wells were trypsinized and counted and the total cpm albumin and stored at -70°C. Periodically an aliquot of each IFN-a bound was normalized for 5 x IO4cells. species was rechecked for antiviral activity which remained virtually Solid Phase RIA. The immunoreactivities of MAbs Bl.l, B72.3, and unchanged with storage at -70*C. Prior to use an aliquot of each was W6/32 were also determined in whole cell extracts with a solid phase thawed, diluted, and added to the growth medium at the indicated RIA. Untreated and interferon-treated MCF-7 cells were routinely antiviral titers. scraped from T-75 flasks and pelleted by centrifugation at 1000 x g. Hybridoma Methodology. The details of the generation and charac The medium was removed and the cell pellet was resuspended and terization of the MAbs B1.1 and B72.3 have been reported (26-28). homogenized for 2-3 rain on ice in 10 mM Tris-HCl (pH 7.2)-0.2 HIM Briefly, B1.1 is an IgG2a that recognizes a M, 180,000 CEA, whereas CaCl2 (10 g, wet weight/100 ml). The homogenate was further disrupted B72.3 is an IgGl that reacts with a high molecular weight (>106) with a cell bomb (Parr Instrument Co., Moline, IL) for 5 min at 1000 glycoprotein antigen complex termed TAG-72.
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