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Cutting Edge: Differential Effect of Apoptotic Versus Necrotic Tumor Cells on Macrophage Antitumor Activities

Isabella Reiter^1,*, Barbara Krammer^* and Günter Schwamberger

^* Institute of Physics and Biophysics and Institute of Chemistry and Biochemistry, University of Salzburg, Salzburg, Austria

	Abstract

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Macrophages (M) play essential roles both in tumor defense and normal tissue homeostasis by removal of transformed as well as damaged and disintegrating cells. Whereas tissue necrosis is known to provoke inflammatory responses, removal of apoptotic cells has been assumed to be immunologically inert. We now show that while M exposure to necrotized tumor cells causes pronounced stimulation of M antitumor activity, exposure of M to apoptotic tumor cells in contrast results in impairment of M-mediated tumor defense and even support of tumor cell growth. Given the fact that apoptosis is a consequence of various cancer treatment modalities, this may lead to a suppression of local antitumor reactions and thus actually counteract endogenous immune-mediated tumor defense mechanisms.

	Introduction

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Apoptosis is a major cause of cell death in health and disease (1). Clearance of apoptotic cells is mainly mediated by macrophages (M)² and has been shown to be accomplished via several recognition mechanisms involving _Vß₃ integrin, CD36, and thrombospondin (2), a putative M receptor for phosphatidylserine exposed on apoptotic cells (3), CD14 (4), as well as other as-yet unidentified receptors (reviewed in Ref. 5). Phagocytosis of apoptotic cells by M has been reported to occur without the induction of inflammatory reactions usually observed with necrotic tissues (4, 5, 6, 7). The absence of an inflammatory response following apoptotic cell death has been attributed to a lack of stimulating signals or to the rapid removal of cells undergoing apoptosis by phagocytes before release of noxious and immunogenic content can occur (8). Conversely, it has been proposed that it is not the apoptotic cells failing to provide pro-inflammatory signals, but that they may actually be able to induce active suppression of inflammatory responses (9). In fact, the presence of apoptotic cells during M activation has recently been shown to increase their secretion of anti-inflammatory mediators and to decrease secretion of pro-inflammatory cytokines (10, 11). Since tumor cell destruction induced by most current cancer treatment regimes (-irradiation, chemotherapy) predominantly results in tumor cell apoptosis (1), we have investigated the effect of M exposure to apoptotic vs necrotic tumor cells on M antitumor effector functions in vitro.

	Materials and Methods

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Materials

All chemicals used were purchased from Sigma (Deisenhofen, Germany). Cell culture media and additives were derived from Biochrom (Berlin, Germany) unless stated otherwise. LPS from Escherichia coli serotype O55:B5 was obtained from Difco Laboratories (Detroit, MI). Recombinant murine IFN- was produced by Genentech (South San Francisco, CA) and kindly provided by Boehringer Ingelheim (Vienna, Austria). FITC-labeled annexin-V was purchased from Boehringer Mannheim (Mannheim, Germany).

Mice

Female C57BL/6 mice raised under specific pathogen-free conditions at the Max-Planck-Institut für Immunbiologie (Freiburg, Germany) were used at 6–8 wk of age.

Culture of bone marrow-derived M (BMM)

Murine BMM were obtained by in vitro differentiation from bone marrow precursor cells under serum-free conditions for 9 days as previously described (12).

Tumor cells

Variants of the murine T-cell lymphoma YAC-1, and the ß–galactosidase-transfected murine mastocytoma P815 (both provided by G. Schwamberger, Freiburg, Germany), were maintained in serum-free medium consisting of 50% IMDM + 50% Ham’s F12 medium, supplemented with bovine insulin (2.5 µg/ml), human holo-transferrin (5 µg/ml), and bovine thyroglobulin (5 µg/ml), all obtained from Sigma.

Induction and analysis of apoptosis and necrosis

Induction of tumor cell apoptosis was achieved by a 5-min pulse of UV-irradiation delivered by a 4 W UV lamp equipped with a 254-nm filter (Vilber-Lourmat, Marne-la-Vallee, France) at a distance of 16 cm. Apoptosis was determined flow cytometrically by annexin-V-FITC/propidium iodide staining (13). Induction of apoptosis was virtually complete (>95%), whereas irradiated cells remained negative for trypan blue staining for about 12 h after UV exposure. Necrosis was induced by two cycles of freeze-thawing in liquid nitrogen as evidenced microscopically by 100% staining with trypan blue. Tumor cells were added to BMM cultures immediately after treatment.

Exposure of BMM to apoptotic or necrotic tumor cells in vitro

For performance of assays, 10⁵ BMM were seeded in microtiter wells in a total volume of 100 µl IMDM. The plates were incubated for 3 h at 37°C in humidified air and 7% CO₂ to allow M adherence to the culture wells. Then 100 µl warm IMDM together with 5 x 10⁴ pretreated P815 tumor cells, negative for alkaline phosphatase (AP), were added. Part of the M cultures were additionally treated with 100 U/ml IFN- and 100 ng/ml LPS. After 24 h, samples of culture medium were removed for nitrite determinations and residual culture medium was replaced by 100 µl warm IMDM before addition of YAC-1 tumor target cells for the M-mediated tumor cytotoxicity assay as described below.

Assay for M-mediated tumor cytotoxicity

The method for determination of M-mediated tumor cytotoxicity is based on the measurement of AP activity specifically expressed by certain tumor cells such as YAC-1 (14). Briefly, 10⁴ YAC-1 target cells in 100 µl warm IHM medium (70% IMDM, 20% Ham’s F12, and 10% 8 mM MgCl₂ in HEPES-buffered saline, supplemented with 1 µg/ml bovine insulin, 2 µg/ml human holo-transferrin, and 2 µg/ml bovine thyroglobulin) were added to BMM pretreated as described above and 96-well plates incubated for another 24 h. Thereafter, plates were centrifuged at 800 x g for 15 min before removal of culture medium for nitrite determination. Subsequently, AP activity of remaining YAC-1 cells was determined as described (14). Assays were performed in triplicates, and cytotoxicity was determined as the percentage reduction of AP activity as compared with untreated controls ± SD. Growth stimulation was calculated as the percentage increase of AP activity compared with control cultures without BMM (15).

Phagocytosis of killed P815 tumor cells by BMM

Clearance of apoptotic or necrotic P815 tumor cells by BMM was measured by colorimetric determination of residual ß-galactosidase activity of killed P815 cells exposed to BMM as compared with killed tumor cells incubated in the absence of BMM, using 2.5 mM nitro-phenyl ß-D-galactopyranoside in 50 mM HEPES buffer (pH 7.8) containing 0.1% Triton X-100 as substrate.

Measurement of the direct influence of killed P815 tumor cells on live YAC-1 tumor target cells

For performance of the assay, different concentrations (6.25 x 10³ to 5 x 10⁴) of apoptotic or necrotic P815 tumor cells were seeded in microtiter wells in a total volume of 100 µl warm IMDM and incubated for 24 h at 37°C. Subsequently, 10⁴ AP-positive YAC-1 tumor cells in 100 µl warm IHM medium were added, and the plates were incubated for another 24 h at 37°C in humidified air and 7% CO₂. Thereafter cytotoxicity was determined based on the measurement of AP activity of YAC-1 tumor cells, as indicated above.

Assay for secretion of nitrite

Nitrite content of BMM culture supernatants, used to assess M NO production, was determined as described by Ding et al. (16) using serial dilutions of sodium nitrite in culture medium as standards.

	Results and Discussion

Top Abstract Introduction Materials and Methods Results and Discussion References

 
As a model system, we used pure murine BMM either quiescent or additionally activated with IFN- and LPS, known to be potent inducers of M antitumor activities (17). M were allowed to interact with killed tumor cells; then live tumor target cells were added, and subsequently M tumor cytotoxicity and secretion of NO, considered to be an important antitumor mediator of M (18), was measured. To exclude interference of the remaining dead but unphagocytosed tumor cells with measurement of M tumor cytotoxicity on added live tumor cells, different cell lines were used for pretreatment and as targets for cytotoxicity.

Exposure of BMM to necrotic tumor cells, as anticipated, resulted in M-mediated cytotoxicity against live tumor target cells of almost 50% by otherwise unstimulated BMM and in a substantial increase in tumor cytotoxicity of BMM treated with IFN- and LPS (Fig. 1a). In contrast, preincubation of BMM with apoptotic tumor cells led to a marked suppression of the tumor cytotoxicity exerted by BMM stimulated with IFN- and LPS. This suppression of antitumor activity was also reflected by a reduced production of NO (Fig. 1b). This result is in line with earlier findings that pre-exposure of M to phosphatidylserine-containing liposomes suppresses activation of M for both tumor cytotoxicity and NO secretion (19, 20). Most notably, however, unstimulated BMM exposed to apoptotic tumor cells even enhanced growth of live tumor cells by more than 40% (Fig. 1a). Similar results were obtained with several types of apoptotic or necrotic cells (YAC-1 lymphoma, Meth A fibrosarcoma, and bone marrow-derived monoblastic cells; data not shown), suggesting that this phenomenon is not peculiar to a certain tumor cell line.

View larger version (26K): [in this window] [in a new window]   FIGURE 1. Effect of necrotic or apoptotic P815 tumor cells on tumor cytotoxicity of murine BMM on YAC-1 tumor target cells (a) measured by AP assay, and secretion of nitrite (b) determined by Griess reaction, as a measure of nitric oxide production. BMM either unstimulated or treated with a combination of IFN- and LPS were exposed simultaneously to either necrotic or apoptotic AP-negative P815 cells. BMM not exposed to dead tumor cells served as control. Concentration of residual particulate cellular material left over from dead P815 cells used for BMM stimulation at the time point of addition of live YAC-1 target cells is depicted in d. Values are given in cell number equivalents, based on residual ß-galactosidase activity as compared with dead P815 cells incubated in the absence of BMM. The full scale reflects original concentrations of dead P815 cells seeded into culture wells. The direct effect of different concentrations of necrotic or apoptotic P815 cells on live YAC-1 cells in the absence of BMM, measured as for M-mediated cytotoxicity, is displayed for comparison in c. Bars represent SD of triplicate samples.

Our observations provide further evidence that apoptotic cells are not immunologically inert, but do have immunosuppressive properties and may indirectly contribute to tumor growth by deactivating M and stimulating them to express a tumor-promoting phenotype. In fact, M isolated from tumor sites have been reported to be defective in tumor cytotoxic effector functions and to be rather supportive to further tumor cell growth (21, 22). Since growing tumors have been described as constituting sites of abnormally elevated apoptotic cell death (9), at least part of the immunosuppressive properties often observed with tumors (22) may be due to the exposure of M to naturally occurring apoptotic tumor cells. Given the predominance of apoptotic cell death in most common cancer treatment regimes (1), this effect may even be markedly enhanced by therapeutic intervention, possibly leading to a total failure of local M-mediated antitumor reactions and in consequence to an impaired endogenous immune-mediated tumor defense. Interestingly, and in accordance with this notion, recent reports have provided evidence for reduced immunogenicity of apoptotic tumor cells as compared with either viable counterparts (23) or cells killed in a nonapoptotic fashion (24). However, since we have observed virtually opposite effects of necrotic tumor cells on M functions, this finding suggests that treatment modalities aimed at inducing tumor cell necrosis instead may more likely result in final eradication of tumors as a consequence of unspecific activation of the immune system.

	Footnotes

 
¹ Address correspondence and reprint requests to Dr. Isabella Reiter, Institute of Physics and Biophysics, University of Salzburg, Hellbrunnerstrasse 34, A-5020 Salzburg, Austria. E-mail address:

² Abbreviations used in this paper: M, macrophage; BMM, bone marrow-derived M; AP, alkaline phosphatase.

Received for publication February 18, 1999. Accepted for publication June 4, 1999.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Reiter, I. Articles by Schwamberger, G. Search for Related Content PubMed PubMed Citation Articles by Reiter, I. Articles by Schwamberger, G. Pubmed/NCBI databases Substance via MeSH