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The Journal of Immunology, 2001, 166: 5878-5881.
Copyright © 2001 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Systemic Inhibition of Angiogenesis Underlies Resistance to Tumors During Acute Toxoplasmosis1

Christopher A. Hunter*, Duonan Yu*, Michael Gee{dagger}, Cam V. Ngo*, Cinzia Sevignani*, Michael Goldschmidt*, Tatyana V. Golovkina§, Sydney Evans{ddagger}, William F. Lee{dagger} and Andrei Thomas-Tikhonenko2,*

Departments of * Pathobiology, {dagger} Medicine, and {ddagger} Clinical Studies, University of Pennsylvania, Philadelphia, PA 19104; and § The Jackson Laboratory, Bar Harbor, ME 04609


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
The ability of various infections to suppress neoplastic growth has been well documented. This phenomenon has been traditionally attributed to infection-induced concomitant, cell-mediated antitumor immunity. We found that infection with Toxoplasma gondii effectively blocked neoplastic growth of a nonimmunogenic B16.F10 melanoma. Moreover, this effect was independent of cytotoxic T or NK cells, production of NO by macrophages, or the function of the cytokines IL-12 and TNF-{alpha}. These findings suggested that antitumor cytotoxicity was not the primary mechanism of resistance. However, infection was accompanied by strong, systemic suppression of angiogenesis, both in a model system and inside the nascent tumor. This suppression resulted in severe hypoxia and avascular necrosis that are incompatible with progressive neoplastic growth. Our results identify the suppression of tumor neovascularization as a novel mechanism critical for infection-induced resistance to tumors.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
The first observation that infection interferes with tumor growth was made by William B. Coley, who noted that streptococcal infection caused regression of soft tissue sarcomas (reprinted in Ref. 1). Subsequent research revealed that other bacterial (Listeria monocytogenes, Corynebacterium parvum, Mycobacterium bovis) and protozoan (Toxoplasma gondii, Besnoitia jellisoni) pathogens nonspecifically activated macrophages to kill tumor cells in vitro (reviewed in Ref. 2) and conferred upon the host resistance to tumors (3, 4, 5). The discovery of other cytotoxic components of innate (NK cells) and adaptive (CTLs) immunity has extended the list of candidates potentially responsible for tumor suppression (reviewed in Ref. 6). However, the contribution of the immune system to the infection-induced resistance to tumors remained unclear. We set out to determine whether stimulation of the immune response underlies resistance to tumor growth in infected animals using acute toxoplasmosis as a model.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Tumor load studies

A total of 1 x 106 tumor cells were injected s.c. in the flanks of syngeneic (C57BL/6J) or immunocompromised (B6.129P2-Nos2tm1Lau, C.B-17 scid-beige, C57BL/6-Pfptm1Sdz, B6.129-Tnfrsf1atm1Mak, and B6.129S1-Il12btm1Jm) animals. Scid-beige mice were obtained from Taconic Farms (Germantown, NY); all other strains were obtained from The Jackson Laboratory (Bar Harbor, ME). Acute infection was initiated by i.p. injection with 15 cysts of the ME49 strain of T. gondii (7).

Matrigel angiogenesis assay

The assay has been described in detail previously (8). As angiogenic stimuli, basic fibroblast growth factor (bFGF)3 (500 ng per pellet; Collaborative Biomedical Products, Bedford, MA) or p53-deficient colonocytes (250,000–500,000 cells per pellet) were used. No less than six Matrigel (Collaborative Biomedical Products) pellets were analyzed in each experiments, and each experiment was repeated at least twice.

Tumor neovascularization and hypoxia studies

To visualize areas of hypoxia and necrosis as well as newly sprouting blood vessels, 3 h before sacrifice animals were injected in the tail veins with EF5 (2-[2-nitro-1H-imidazol-1-yl]-N-(2,2,3,3,3-pentafluoropropyl)acetamide; provided by C. J. Koch, University of Pennsylvania). Frozen sections of excised tumors were stained with a Cy3-conjugated Ab against EF5 (9) and a mAb against platelet-endothelial cell adhesion molecule (PECAM)/CD31 (BD PharMingen, San Diego, CA). Slides were counterstained with hematoxylin to reveal areas of viable and necrotic cells. To visualize the architecture of blood vessels in nascent neoplasms, 15 min before sacrifice animals were injected into the tail veins with FITC-conjugated tomato lectin (Vector Laboratories, Burlingame, CA). Then 1-mm-thick sections were examined using confocal microscopy (10).


   Results and Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
To investigate the connection between acute infection and resistance to tumors, mice were infected with T. gondii and challenged with the B16.F10 melanoma cells that on their own are very weakly, if at all, immunogenic (11). When injected s.c. in syngeneic C57BL/6 mice, these cells form rapidly growing tumors reaching ~0.5 g in 10–12 days. However, in animals infected with T. gondii on the day of tumor implantation, tumor growth was severely suppressed (Fig. 1GoA). Histopathological analysis revealed that while B16 tumors from uninfected animals (Fig. 1GoB) possessed adequate vasculature (yellow arrows) and typically exhibit only small areas of focal necrosis, B16 cell masses from animals infected for 12 days are largely nonviable (Fig. 1GoC). In the experiment depicted in Fig. 1GoD, the weights of these abortive tumors did not exceed 15 mg, ~10% of the neoplasms from uninfected mice. To demonstrate that this inhibitory effect is applicable to other neoplastic cells, we performed the same experiment with murine colonocytes transformed in vitro by the Ki-Ras2 oncogene (12), which bears the nonimmunogenic G-to-V mutation (13, 14). These cells are normally tumorigenic, but in infected mice formed only small masses whose average weight did not exceed 30 mg (Fig. 1GoE). Thus, infection of mice with T. gondii effectively inhibited neoplastic growth.



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  		FIGURE 1. Characterization of the tumors developing during acute infection. A, Gross appearance of B16 melanomas forming in normal (top) and T. gondii (Tg)-infected (bottom) C57BL/6J mice 12 days postimplantation. B and C, Histopathological (hematoxylin and eosin) staining of the specimens depicted in A, top and bottom, respectively. Yellow arrows in B point at perfused blood vessels. D–J, Average weights of tumors formed by B16.F10 (D and F–J) and Ras-transformed colonocytes (E) in control and T. gondii (Tg)-infected mice. Each panel represents an individual experiment in which no less than six tumors per group were analyzed. Error bars represent SEs of the mean. All differences in tumor weights between infected and control animals are highly statistically significant per Student’s t test, with p < 0.0001. Each experiment has been repeated at least twice, with comparable results. Data in F–J were obtained using indicated strains of immunocompromised mice.

 
To assess whether cytotoxic functions associated with innate or adaptive immunity contribute to this inhibition, mice deficient in different immune components were used for tumor load studies. Infection with T. gondii has been shown to result in the activation of macrophages to nonspecifically kill tumor cells in vitro (2). Macrophages destroy tumor cells using two principal mediators, NO produced by the enzyme inducible NO synthase and TNF-{alpha} (15, 16). Because B16 melanomas cells are sensitive to NO but not TNF-{alpha} (17), mice lacking inducible NO synthase (18) were chosen for further studies. In addition, neoplastic cells could be destroyed by CTLs and NK cells; thus we also used scid-beige mice where CTLs are absent and NK cells are not cytotoxic, and perforin (Pfp) knockout mice where cytolytic functions are essentially absent (19). In all three strains, the ability of T. gondii to suppress tumor growth was evident: while absolute tumor weights varied in different strains, the ratios of tumor weights in uninfected and infected animals were equivalent to that observed in wild-type animals (Fig. 1Go, F–H). We have also analyzed strains of mice deficient in two major immunomodulatory pathways, TNF-{alpha} and IL-12, that are required for activation of macrophages, T cells, and NK cells and have been implicated in immunity to tumors. Their functions are disrupted in animals lacking the p40 subunit of IL-12 (20) and the type 1 TNF-{alpha} receptor (21). Nonetheless, infection with T. gondii still suppressed tumor growth in both of these strains (Fig. 1Go, I and J). Together, these data indicated that most of the major cytotoxic mechanisms implicated in tumor surveillance are not required for infection-induced resistance to tumors. This implied the existence of an alternative, noncytotoxic mechanism responsible for tumor suppression.

Histological analysis of abortive tumors from infected animals revealed that, in addition to being necrotic, these masses conspicuously lacked blood vessels (Fig. 1Go, B and C). Because insufficient tumor vascularization could be due to suppression of angiogenesis during infection, in vivo Matrigel neovascularization experiments were performed. bFGF was used as an angiogenic stimulus in A/J mice. The assay was quantitated by determining hemoglobin content of "empty" or bFGF-containing Matrigel pellets. As shown in Fig. 2GoA, Matrigel pellets containing bFGF were vascular and rich in hemoglobin in uninfected mice but not in animals infected with T. gondii; the latter contained only baseline amounts of hemoglobin characteristic of "empty" Matrigel pellets. bFGF is a poor inducer of angiogenesis in C57BL/6J mice (Ref. 22 and data not shown), and B16 cells themselves cannot be used for Matrigel experiments because the presence of melanin interferes with the hemoglobin assay. Therefore, primary colonocytes from p53-/- C57BL/6J mice were used as an angiogenic stimulus. When embedded in Matrigel, these immortalized but nontumorigenic colonocytes stimulated robust neovascularization, as indicated by high hemoglobin content (Fig. 2GoB). Colonocyte-induced neovascularization was largely suppressed when Matrigel-bearing animals were infected with T. gondii (Fig. 2GoB). Histopathological staining of excised pellets confirmed that in uninfected but not in T. gondii-infected animals, Matrigel pellets contain vascular channels that were well perfused, as judged by the presence of erythrocytes (Fig. 2Go, C and D, yellow arrows). Together, these results indicate that infection with T. gondii results in systemic suppression of angiogenesis that potentially could cause insufficient tumor vascularization and stunt neoplastic growth.



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  		FIGURE 2. Neovascularization of Matrigel implants during acute infection. A, Average hemoglobin contents of bFGF-containing Matrigel pellets in normal and T. gondii (Tg)-infected A/J mice. Bars 1 and 2 and the dotted line refer to "empty" Matrigels, bars 2 and 4 to Matrigels containing 500 ng of basic FGF. B, Average hemoglobin contents of p53-deficient colonocytes containing Matrigels pellets in normal and T. gondii (Tg)-infected mice. C and D, Histopathological staining of the Matrigels analyzed for hemoglobin content in B, left and right, respectively. Yellow arrows in C point at perfused vascular spaces. Note the presence of acinar structures (blue arrows) that are formed by differentiating colonocytes.

 
To compare and contrast tumor vascularization in infected and uninfected mice, we examined small, nascent tumors earlier in infection, before wide-spread necrosis developed and while they were still similar in size to tumors in normal animals. Therefore, animals infected with T. gondii were used on day 7 or 8 postimplantation and control animals were used on day 5 or 6. The use of different time points ensured that tumors did not differ in size by >50%. Furthermore, at these time points B16 cell masses were largely composed of viable, melanin-producing cells both in uninfected and infected animals (Fig. 3Go, A and B, outside red dashed line). To assess the level of hypoxia in these size-matched cell masses, animals were injected i.v. with EF5. EF5 is a compound that is taken up by all perfused tissues but only in hypoxic cells is it converted into immunohistochemically detectable adducts (23). Subsequent staining with an Ab against EF5 adducts revealed extensive areas of hypoxia in tumors from infected mice (Fig. 3GoD), whereas in control tumors no EF5 staining was apparent (Fig. 3GoC). Characteristically, all contiguous areas of hypoxia surrounded areas of necrosis (inside the dashed lines, Fig. 3Go, B and D) that lacked viable, melanin-producing cells; no such areas were found in tumors from uninfected mice (Fig. 3GoC).



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  		FIGURE 3. Tumor neovascularization and hypoxia during acute infection. All images in the left column refer to small B16 tumors formed in normal mice; all images in the right column refer to small tumor masses formed in T. gondii-infected mice. A–F represent frozen sections; G and H represent live tissues. A, C, and E correspond to the same microscopic field, as do images B, D, and F. A and B, Bright field microscopy of frozen sections of B16 tumors developing in normal and infected mice, respectively. Brown staining is melanin produced by live B16 cells. The unstained area in B outlined by the red dashed line is the area of tumor necrosis, with no viable cells. C and D, Immunohistochemical staining of hypoxic region using an Ab against EF5 adducts. The area within the dashed line in D is identical with the area outlined by the red dashed line in B. E and F, Immunohistochemical staining of nascent blood vessel using an Ab against the CD31/PECAM surface marker of endothelial cells. G and H, Staining of perfused blood vessels by FITC-conjugated lectin as revealed by confocal microscopy and superimposition of up to 25 computer images corresponding to the same field at focal planes separated by 5 µm. The original green FITC color has been digitally converted to red. All analyses have been repeated on four additional tumors, with comparable results obtained in all experiments.

 
Because tumor hypoxia is likely to result from an inadequate blood supply (24), studies were performed to assess how infection with T. gondii affects growth of new blood vessels. Tumor sections from the previous experiment were counterstained with an anti-PECAM/CD31 mAb, which is reactive with capillary endothelial cells. While tumors developing in control animals stained positively for this marker (Fig. 3GoE), tumors from infected animals exhibited only diffuse background staining (Fig. 3GoF). To demonstrate that these CD31-positive endothelial cells are part of a functional vascular system, tumor-bearing animals were injected i.v. with FITC-conjugated lectin. This compound binds to endothelial cells in all perfused tissues, allowing for computer-assisted three-dimensional reconstruction of the vascular system in nascent neoplasms. In control animals, B16 tumors possessed elaborate vasculature, with small vessels branching off larger ones (Fig. 3GoG), whereas no contiguous vascular system was apparent in tumors from infected animals (Fig. 3GoH). The spatial correlation between insufficient neovascularization, hypoxia, and necrosis strongly suggests that inhibition of angiogenesis during infection is crucial for resistance to tumors. Interestingly, this conclusion is in agreement with the data from the 1940s that treatment with bacterial LPSs negatively affects tumor vascularity (25).

It has long been assumed that resistance to tumors during infection could be explained by concomitant, cell-mediated antitumor immunity. Our results indicate that resistance requires neither the effector function of cytotoxic cells (macrophages, CTLs, and NK cells) nor the two major cytokines (TNF-{alpha} and IL-12) that activate them. Nevertheless, besides being able to lyse neoplastic cells, immune cells also secrete soluble factors that can stunt tumor growth indirectly, for instance via suppression of angiogenesis. The existence of such soluble anti-angiogenic factors is supported by the fact that plasma from infected but not control mice blocks formation of tube-like structure by endothelial cells in vitro on the surface of Matrigel (data not shown). Moreover, several cytokines systemically produced during acute toxoplasmosis have been reported to possess anti-angiogenic properties, most notably type I and type II IFNs (26, 27). Although our preliminary data indicate that separate neutralization of IFN-{gamma} and IFN-{alpha}{beta} does not restore angiogenesis in infected animals, their combined action might be responsible for insufficient tumor vascularization. This concept is illustrated by the ability of TNF-{alpha} to suppress neovascularization in conjunction with IFN-{gamma} (28). Interferon-{gamma} is also known to activate IFN-{gamma}-inducible protein 10, a chemokine implicated in both resistance to T. gondii (29) and suppression of angiogenesis (30).

Identification of an infection-induced soluble factor(s) responsible for suppression of angiogenesis and, by inference, tumor growth would have important therapeutic implications. T. gondii is unlikely to be useful for treatment of cancer. In our experimental system, after the acute phase of infection is over, the remaining viable cells resume neoplastic growth. Moreover, in many cancer patients toxoplasmosis is a life-threatening illness (31). In contrast, systemic administration of a soluble anti-angiogenic factor could be maintained indefinitely, might not result in acquired drug resistance (32), and has proven successful in treating experimental neoplasms (33, 34, 35). Understanding the molecular basis for infection-mediated suppression of angiogenesis might be instrumental in identifying new inhibitors of tumor vascularization and developing new treatments for cancer.


   Footnotes
 
1 This work has been supported by grants from the National Institute of Allergy and Infectious Diseases (AI42334, to C.A.H.), National Cancer Institute (CA71881, to A.T.-T.), and from the University of Pennsylvania Cancer Center (to A.T.-T.). Back

2 Address correspondence and reprint requests to Dr. Andrei Thomas-Tikhonenko, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6051. Back

3 Abbreviations used in this paper: bFGF, basic fibroblast growth factor; PECAM, platelet-endothelial cell adhesion molecule. Back

Received for publication December 27, 2000. Accepted for publication March 16, 2001.


   References
Top
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 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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