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The Journal of Immunology, 2000, 165: 6024-6028.
Copyright © 2000 by The American Association of Immunologists

CUTTING EDGE

Spontaneous Rejection of Poorly Immunogenic P1.HTR Tumors by Stat6-Deficient Mice1

Aalok K. Kacha*, Francesca Fallarino*, Mary A. Markiewicz* and Thomas F. Gajewski2,*,{dagger}

* Department of Pathology and the Committee on Immunology, and {dagger} Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Experimental evidence suggests that a type 1 T cell response may result in optimal tumor rejection in vivo. This phenotype is determined in part by cytokines that influence T cell differentiation. In transplantable tumor models such as P1.HTR, tumors grow progressively despite expression of defined tumor Ags. We hypothesized that this failure to reject may be due to poor generation of a type 1 phenotype, through a dominant influence of the type 2-promoting cytokines IL-4 and/or IL-13. This hypothesis was tested by implanting P1.HTR tumors into mice deficient in Stat6. In contrast to progressive growth of P1.HTR tumors in wild-type mice, and aggressive growth even of IL-12-transfected P1.HTR in Stat1-/- mice, P1.HTR was spontaneously rejected by Stat6-/- mice. Rejection was accompanied by augmented tumor-specific IFN-{gamma} production and CTL activity. These results suggest that pharmacologic inhibition of Stat6 signaling could potentiate anti-tumor immunity in vivo.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
In multiple transplantable tumor models, tumors grow progressively in immunocompetent syngeneic mice despite expression of defined tumor Ags that mediate recognition by specific CD8+ CTL (1, 2). In virtually all of these cases, the same tumors are rejected if the mice are pre-immunized against those Ags using a variety of vaccination strategies (3, 4), arguing that the tumor cells themselves are not inherently resistant to a properly generated effector T cell population. These collective observations have implicated a failure to generate and/or maintain tumor-specific effector cells as a primary cause of tumor outgrowth. Multiple hypotheses have been proposed to explain the failure of an effective anti-tumor T cell response to arise spontaneously, including global immunosuppression (5), tumor-specific anergy (6), insufficient CD4+ T cell help (7), apoptosis of tumor-specific effector cells (8), recruitment of other inhibitory cell types such as granulocytes (9), and a barrier effect of the tumor stroma (10). In addition to these possibilities, we have observed that the presence of T cells producing high levels of IFN-{gamma} in lymph nodes draining a tumor site correlates with tumor rejection, suggesting that deficient T cell differentiation into a Th1/Tc1 (type 1) effector population may comprise another mechanism for failed tumor rejection (11). Additional evidence supporting an important role for type 1 T cell responses comes from the observations that neutralization of endogenous IL-12 prevents spontaneous rejection of immunogenic tumors (11), that Stat1-deficient mice (defective in IFN signaling) also fail to reject tumors (12, 13), and that the inclusion of IL-12 in tumor-specific vaccine strategies can induce potent rejection of pre-established tumors in vivo (2, 14).

The reason why a type 1 T cell response might fail to be generated spontaneously in vivo is not clear. One potential mechanism might be through the dominant activity of factors that antagonize T cell differentiation down a type 1 pathway. In vitro, the cytokine IL-4 has been shown not only to promote CD4+ T cell differentiation into Th2 cells, but also to inhibit the ability of low doses of IL-12 to induce development of Th1 cells (15). More recently, IL-13 has been shown to share some properties with IL-4, but also to exert additional, nonoverlapping activities, which are critical for particular immune-mediated processes in vivo. Specifically, IL-13 has been shown to be necessary for the Th2-directed lung inflammation in mouse models of asthma (16), for clearance of intestinal nematodes (17), and for granuloma formation in response to Schistosoma eggs (18). Based on these collective observations, it is conceivable that the combined activities of both IL-4 and IL-13 contribute to imposing a brake on type 1 T cell responses in mouse models of tumor immunity.

One strategy to minimize the activities of both IL-4 and IL-13 is to eliminate a signaling molecule central to the biochemical response to both cytokines. In addition to sharing one receptor component (19), both IL-4 and IL-13 use Stat6 to mediate signals leading to gene transcription (20). Stat6-deficient mice have been generated by homologous recombination, and have been shown to be severely deficient in the biologic response to both IL-4 and IL-13 (21, 22). In vivo, Stat6-deficient mice are resistant to Leishmania infection (23), are resistant in asthma models (24), and show defective contact hypersensitivity (25), all consistent with diminished type 2-mediated immunity.

To determine whether elimination of IL-4 and IL-13 activities could potentiate anti-tumor immunity, P1.HTR tumors were implanted into Stat6-deficient mice. We show that this poorly immunogenic tumor was spontaneously rejected by Stat6-/- mice but not by Stat6+/+ control littermates, and that tumor rejection was associated with increased specific CTL activity and IFN-{gamma} production. These results suggest that pharmacologic inhibition of Stat6 signaling could provide a strategy for potentiating the immune response against tumors in vivo.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice

Stat1-deficient mice were generated as described previously (26) and generously provided by Dr. David Levy (New York University, New York, NY). Stat6-deficient mice were obtained from Dr. Michael Grusby (21). In each case, mice were backcrossed for six generations onto DBA/2 mice (The Jackson Laboratory, Bar Harbor, ME). Heterozygous mice were intercrossed to obtain wild-type (+/+), heterozygous (+/-), and homozygous knockout (-/-) animals. All mice were maintained under specific pathogen-free conditions in a barrier facility at the University of Chicago. Mice between 6 and 10 wk of age were used for experiments. PCR of tail DNA was used to identify mice carrying the targeted Stat1 or Stat6 genes. For Stat1, a set of three primers was used for PCR analysis: P1 (5'-GAGATAATTCACAAAATCAGAGAG-3'), P2 (5'-CTGATCCAGGCAGGCGTTG-3'), and P3 (5'-TAATGTTTCATAGTTGGATATCAT-3'). Thirty-five cycles were performed, using an annealing temperature of 50°C. For Stat6, independent primer pairs were used to amplify thewild-type Stat6 gene and the inserted neomycin gene. The Stat6-specific primers were 5'-TGCTGGGCCGAGGCTTCACATTT-3' and 5'-TATCTGTGAGGAGCCATCCTGAC-3', and the neomycin-specific primers were 5'-GCCCGGTTCTTTTTGTCAAGACCGA-3' and 5'-ATCCTCGCCGTCGGGCATGCGCGCC-3'. For each of these, 45 cycles were performed at an annealing temperature of 55°C. PCR products were resolved using 1.5–2% agarose gels and visualized by ethidium bromide staining. Bands of distinct sizes corresponded to the wild-type and targeted alleles.

Cells

Two variants of the mastocytoma P815 were used in this study: P1.HTR, a highly transfectable variant of P815 (27), and P511, a subclone of P815 known to express the tumor Ag P1A. HTR.B7-1 and HTR.IL-12 (and a control transfectant expressing empty vector, HTR.C) were generated by transfection of P1.HTR cells as described previously (2, 28). The irrelevant syngeneic tumor L1210, which lacks expression of the known P815 Ags, was used as a control target.

In vivo tumor experiments

Cultured tumor cells were washed three times with Dulbecco’s PBS (DPBS),3 and 106 living cells were injected s.c. in 100 µl DPBS via a 27-gauge needle on the left flank. tumor size was assessed twice per week using calipers, the longest and shortest diameters were measured, and a mean was calculated. Data from groups of three to seven mice were analyzed at each time point, and a mean and SE were determined. Measurements continued for 3–4 wk, after which time the mice were sacrificed and the spleens were removed for restimulation in a mixed lymphocyte-tumor culture (MLTC).

MLTC and cytolytic assay

Splenocytes (5 x 106) from immunized or control mice were stimulated with irradiated (10,000 rad) HTR.B7-1 cells (2.5 x 105) in a volume of 2 ml, and 5–6 days later effector function was analyzed. For cytolytic assays, unfractionated cells from the MLTC were washed, adjusted to 2 x 106/ml, and titrated in duplicate in V-bottom microtiter plates along with 2000 51Cr-labeled target cells. Supernatants were collected after 4 h, and transferred to 96-well LumaPlates (Packard, Meridien, CT). After overnight incubation to allow drying, radioactivity was measured using a microplate scintillation counter (Packard). Percent specific lysis was calculated using standard methods.

Lymph node stimulations and functional assays

For analysis of cytokine production, mice were injected into each hind footpad with 106 living HTR.C cells in 50 µl DPBS; control mice received DPBS. After 5 days, the draining popliteal lymph nodes were harvested and single cell suspensions were prepared. Cells (106) were incubated in the presence or absence of 2.5 x 105 irradiated (10,000 rad) HTR.B7-1 cells, supernatants were harvested after 48 h, and residual cells were removed by centrifugation. IFN-{gamma} and IL-4 concentrations were determined using an ELISA with Ab pairs obtained from PharMingen (San Diego, CA). Concentrations were expressed in units per milliliter as determined by the respective recombinant cytokines as standards. For cytolytic assays, mice were injected with 106 HTR.IL-12 cells, and 5 days later, the draining popliteal lymph nodes were removed and analyzed for P815-specific cytolytic activity directly ex vivo, without in vitro expansion.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
IL-12-transfected P1.HTR tumors are rejected by wild-type mice but not by Stat1-/- mice

We have shown previously that the highly transfectable variant of the P815 mastocytoma, P1.HTR, grows progressively in the majority of syngeneic DBA/2 mice (28). This growth does not appear to result from global or tumor-specific immunosuppression, as mice bearing large pre-established tumors on one flank can reject B7-1-transfected tumors on the opposite flank (2). To determine whether augmentation of a type 1 T cell response could enable rejection of this tumor, transfection to express murine IL-12 p35 and p40 cDNAs was performed. As shown in Fig. 1GoA, IL-12-transfected P1.HTR tumors were rejected in normal DBA/2 mice but grew progressively in irradiated mice, supporting rejection by an immunologic mechanism. Control-transfected tumors grew progressively (data not shown; see also Fig. 2Go). Mice that rejected IL-12 transfectants subsequently rejected challenge with wild-type P1.HTR cells 1 mo later, consistent with immunologic memory (data not shown).



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  		FIGURE 1. A, IL-12-transfected variants of P1.HTR are rejected. HTR.IL-12 cells (106 cells/mouse) were implanted s.c. in normal DBA/2 mice (•) or sublethally irradiated (600 rad) DBA/2 mice (3–5 mice/group). The mean tumor diameter was determined on the indicated days. Results are representative of four experiments. B, IL-12-transfected P1.HTR cells fail to be rejected by Stat1-deficient mice. HTR.IL-12 cells (106) were implanted s.c. into Stat1-/- mice that had been bred onto the DBA/2 background, and the mean tumor diameter was determined on the indicated days. Similar results were seen in two independent experiments.

 


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  		FIGURE 2. Stat6-/- mice spontaneously reject P1.HTR tumors. P1.HTR cells (106 cells/mouse) were implanted s.c. in the left flank of Stat6+/+, Stat6+/-, and Stat6-/- mice (5 mice/group). The mean tumor diameter was determined on the indicated days. Results are representative of at least two experiments.

 
Given the demonstrated importance of host IFN signaling in immune-mediated tumor rejection (13), the ability of Stat1-/- mice to reject IL-12-expressing tumors was examined. In fact, IL-12-transfected P1.HTR tumors grew progressively in Stat1-deficient mice (Fig. 1GoB), arguing for a vital role for host IFN signaling in controlling tumor growth promoted by IL-12. Collectively, these results support the importance of type 1 T cell responses in promoting tumor rejection.

P1.HTR is spontaneously rejected by Stat6-/- mice

Inasmuch as promotion of a type 1 T cell response by IL-12 could enable rejection of P1.HTR cells, it was conceivable that elimination of an endogenous inhibitory factor for type 1 differentiation could have a similar consequence. IL-4 has been shown not only to promote type 2 T cell responses but also to inhibit T cell differentiation into type 1 effector cells (15). As IL-13 has been shown to share some functional properties with IL-4 (29), it was desirable to use a strategy to eliminate activity of both cytokines in vivo. To this end, mice deficient in Stat6, which is required for signaling by both IL-4 and IL-13, were employed as tumor recipients. As shown in Fig. 2Go, although P1.HTR tumors grew progressively in Stat6+/+ mice, there was slowing of tumor growth in Stat6+/- mice, and complete rejection in Stat6-/- littermates. Thus, elimination of Stat6 signaling on host cells was sufficient to enable spontaneous rejection of this normally progressively growing tumor.

Effector cells isolated from Stat6-/- mice have increased lytic activity and produce increased levels of IFN-{gamma}

To determine whether absence of host Stat6 resulted in improved T cell differentiation into a cytolytic type 1 phenotype, spleen cells were isolated from all groups of mice after the Stat6-/- animals had rejected. These were restimulated in vitro for 5 days with HTR.B7-1 cells, and cytolytic activity was measured against 51Cr-labeled P511 cells in the presence of unlabeled L1210 cells to eliminate nonspecific lysis. As shown in Fig. 3GoA, substantially greater tumor-specific cytolytic activity was observed from Stat6-/- mice compared with Stat6+/+ littermates. CTL activity from heterozygous mice was intermediate in magnitude.



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  		FIGURE 3. A, Rejection of P1.HTR by Stat6-/- mice correlates with increased tumor-specific lytic activity. Stat6+/+, Stat6+/-, and Stat6-/- mice (5–7 mice/group) were inoculated with 106 P1.HTR tumor cells in the left flank. Four weeks later, splenocytes were prepared and restimulated in vitro with HTR.B7-1 cells, and cytolytic activity was determined against 51Cr-labeled P511 cells in the presence of cold L1210 cells. B, Increased lytic activity in immunized Stat6-/- mice. Wild-type mice, Stat1-/- mice, and Stat6-/- mice were immunized once in the hind footpad with HTR.IL-12 cells. Five days later, draining popliteal lymph nodes were removed and analyzed directly ex vivo for cytolytic activity against 51Cr-labeled P511 cells in the presence of cold L1210 cells. Similar results were seen in three independent experiments.

 
As an alternative approach, Stat6+/+ and Stat6-/- mice were immunized with HTR.IL-12 cells in the hind footpad, and draining popliteal lymph nodes were analyzed directly ex vivo for P815-specific cytolytic activity. Stat1-/- mice were also analyzed as comparison. A single immunization with HTR.IL-12 cells was not sufficient to induce detectable CTL activity in Stat6+/+ mice. However, significant cytolytic activity was routinely detected in Stat6-/- mice (Fig. 3GoB). These results indicate that Stat6-/- mice may more readily support development of T cells with a lytic phenotype.

To examine the cytokine profile of tumor-specific effector T cells in this system, P1.HTR tumors were implanted into the hind footpads of Stat6+/+ and Stat6-/- mice, and popliteal lymph node cells were isolated 5 days later. These were then stimulated in vitro with HTR.B7-1 cells, and supernatants were assessed for presence of IFN-{gamma} and IL-4. As depicted in Fig. 4GoA, substantially greater levels of IFN-{gamma} were produced by lymph node cells isolated from Stat6-/- mice than by those isolated from Stat6+/+ littermates. In no instance was IL-4 detected at appreciable levels (Fig. 4GoB). These results indicate that the absence of host Stat6 signaling results in improved generation of type 1 effector cells, but that the presence of Stat6 in wild-type mice did not result in the induction of detectable tumor-specific T cells that produce IL-4.



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  		FIGURE 4. Tumor-specific T cells from Stat6-/- mice produce increased levels of IFN-{gamma}. Stat6+/+ and Stat6-/- mice (3 mice/group) were inoculated with either P1.HTR cells (106) or DPBS in the hind footpad. After 5 days, the draining popliteal lymph nodes were harvested, and single cell suspensions were prepared and stimulated with HTR.B7-1 cells. Supernatants were collected at 48 h and assayed for the content of IFN-{gamma} (A) and IL-4 (B). Similar results were obtained in two independent experiments.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Although multiple hypotheses have been proposed to explain why tumors expressing defined Ags nonetheless grow progressively in vivo, our current results provide evidence that one mechanism may be lack of effective induction or maintenance of type 1 T cell responses. Relief of inhibitory signals for type 1 T cell differentiation through Stat6 was sufficient to enable rejection of a tumor that normally grows progressively. Thus, in this tumor model, factors intrinsic to the immune system are limiting the ability of that immune system to eliminate a growing tumor. These results do not exclude other mechanisms from contributing to immune escape in other tumor models, such as production of TGF-{beta} or FasL by tumor cells.

It is not yet known whether the antagonistic factor limiting anti-tumor immunity in wild-type mice is IL-4, IL-13, or both. It is of interest that other model systems have not demonstrated improved tumor rejection in the absence of IL-4 (30), suggesting that IL-13 is an attractive candidate. As it appears that functional IL-13 receptors are not expressed by T cells (29), the hypothetical effect of IL-13 would likely be indirect through another cell type. The source of IL-4 and/or IL-13 also is not clear, as we have not detected significant production of Th2 cytokines by tumor-specific T cells in this model. Low levels of basal IL-4 and/or IL-13 production by nontumor-reactive T cells or by non-T cells could provide sufficient activity to mediate this block on type 1 T cell development.

It is of interest that Stat6+/- mice showed a phenotype that was intermediate between those of the Stat6+/+ and Stat6-/- animals, with partial slowing of tumor growth and a modest increase in CTL activity observed. These results are consistent with a Stat6 gene dosage effect. Inasmuch as the Stat6-/- mice were backcrossed six generations onto the DBA/2 background, it is conceivable that a gene other than the targeted Stat6 locus is mediating the increased tumor rejection observed. This is unlikely, as we observed progressive tumor growth in Stat6+/+ littermate controls. However, the possibility that a gene tightly linked to Stat6 is mediating this effect cannot be entirely excluded.

Although multiple experimental tumor models have supported a dominant role for type 1 T cell responses in promoting optimal tumor rejection, some models have demonstrated a contribution of type 2 cytokines as well. This role has been most clearly demonstrated in experiments using GM-CSF-transfected tumor cells as a vaccination strategy, in which eosinophils driven by IL-4 and IL-5 appear to contribute to the effector phase of the immune response (30). However, rejection of many tumor types has been shown to be promoted by IL-12-based treatment strategies (2, 14), and endogenous IL-12 and IFN are important for the spontaneous rejection of immunogenic tumors (11, 13). In the P1.HTR model, there is a clear hierarchy of rejection potential by mouse genetic variants, with Stat6-/- DBA/2 mice being superior to wild-type DBA/2 mice, which in turn are superior to Stat1-/- DBA/2 mice at rejecting tumors. These observations suggest that Stat1 and Stat6 signaling pathways should be examined in patients with advanced cancer for possible alterations, which if perturbed could either contribute to poor tumor rejection or be caused by the presence of large tumor masses. The development of pharmacologic agents that target Stat6-dependent signal transduction could have applicability in the immunotherapy of cancer.


   Acknowledgments
 
The authors thank Drs. D. Levy and M. Grusby for providing the Stat1- and Stat6-deficient mice, respectively, and E. Marshall for assistance with mouse screening.


   Footnotes
 
1 This work was supported in part by a McDonnell Scholar Award in Molecular Oncology, and by the Burroughs-Welcome Fund. A.K.K. was supported by the Medical Scientist National Service Research Award 5T32 GM07281. Back

2 Address correspondence and reprint requests to Dr. Thomas F. Gajewski, University of Chicago, 5841 South Maryland Avenue, MC2115, Chicago, IL, 60637. Back

3 Abbreviations used in this paper: DPBS, Dulbecco’s PBS; MLTC, mixed lymphocyte-tumor culture. Back

Received for publication August 24, 2000. Accepted for publication October 12, 2000.


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 Discussion
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IL-4-Transfected Tumor Cell Vaccines Activate Tumor-Infiltrating Dendritic Cells and Promote Type-1 Immunity
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Tc1 and Tc2 Effector Cell Therapy Elicit Long-Term Tumor Immunity by Contrasting Mechanisms That Result in Complementary Endogenous Type 1 Antitumor Responses
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M. Terabe, S. Matsui, J.-M. Park, M. Mamura, N. Noben-Trauth, D. D. Donaldson, W. Chen, S. M. Wahl, S. Ledbetter, B. Pratt, et al.
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S. M. Jensen, S. L. Meijer, R. A. Kurt, W. J. Urba, H.-M. Hu, and B. A. Fox
Regression of a Mammary Adenocarcinoma in STAT6-/- Mice Is Dependent on the Presence of STAT6-Reactive T Cells
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S. Ostrand-Rosenberg, V. K. Clements, M. Terabe, J. M. Park, J. A. Berzofsky, and S. K. Dissanayake
Resistance to Metastatic Disease in STAT6-Deficient Mice Requires Hemopoietic and Nonhemopoietic Cells and Is IFN-{gamma} Dependent
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M. A. Sherman, D. R. Powell, and M. A. Brown
IL-4 Induces the Proteolytic Processing of Mast Cell STAT6
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H. Harlin, E. Podack, M. Boothby, and M.-L. Alegre
TCR-Independent CD30 Signaling Selectively Induces IL-13 Production Via a TNF Receptor-Associated Factor/p38 Mitogen-Activated Protein Kinase-Dependent Mechanism
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P. Nanni, G. Nicoletti, C. De Giovanni, L. Landuzzi, E. Di Carlo, F. Cavallo, S. M. Pupa, I. Rossi, M. P. Colombo, C. Ricci, et al.
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M. J. Dobrzanski, J. B. Reome, and R. W. Dutton
Role of Effector Cell-Derived IL-4, IL-5, and Perforin in Early and Late Stages of Type 2 CD8 Effector Cell-Mediated Tumor Rejection
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