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CUTTING EDGE |
*
Department of Biological Sciences, University of Maryland, Baltimore, MD 21250; and
Department of Immunology and Infectious Diseases, Harvard School of Public Health, and Department of Medicine, Harvard Medical School, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Th1 cells are generally considered to provide "help" to CD8+ T cells, whereas Th2 cells provide "help" to Ab-producing B cells (17). This paradigm has been extended to tumor immunity, and investigators have proposed that Th1 cells are the desired CD4+ population because they facilitate differentiation of tumor-specific CD8+ T cells (18, 19), which are potent anti-tumor effectors (20). Although the correlation between STAT4-/- and STAT6-/- mice and deficiencies in Th1 and Th2 cells, respectively, is not absolute, we speculated that these mice might provide useful information on the roles of Th1 and Th2 cells in anti-tumor immunity. We challenged BALB/c STAT4-/- and STAT6-/- mice in the mammary gland with the highly malignant, nonimmunogenic, and metastatic BALB/c-derived 4T1 mammary carcinoma (21, 22, 23). Our expectation was that STAT6-/- mice would have enhanced anti-tumor immunity because differentiation of CD4+ T cells would be skewed toward a Th1 response and that STAT4-/- mice would have reduced anti-tumor immunity because they are deficient for Th1 cells. We observed that the 4T1 tumor grows and metastasizes less in STAT6-/- mice, suggesting that deletion of the STAT6 gene enhances anti-tumor immunity. Surprisingly, however, the STAT6-/- effect is independent of Th1 or Th2 cells, suggesting that the STAT6 gene negatively regulates tumor growth via a CD4+ T cell-independent mechanism.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c STAT6-/- (5) and STAT4-/- (14) mice were bred in the University of Maryland Baltimore County (UMBC) Biology Department animal facility. These mice were generated by targeted disruption of the STAT6 and STAT4 genes, respectively, in 129 strain mice. Offspring were backcrossed for 10 generations to BALB/c mice. STAT6-/- and STAT4-/- mice have no detectable STAT6 or STAT4 protein, respectively. BALB/c mice were either purchased from The Jackson Laboratory (Bar Harbor, ME), and/or bred at UMBC and maintained in accordance with National Institutes of Health guidelines for the humane treatment of laboratory animals. Mice were challenged in the abdominal mammary gland with 7 x 103 wild-type 4T1 tumor cells. Primary tumors at the site of injection were measured using an electronic calipers and tumor diameters calculated as the square root of the length x width of the tumor as previously described (24). Number of clonogenic lung metastases was determined by plating dissociated lung cells in medium supplemented with 6-TG, as previously described (24). Data presented are representative of three independent primary tumor challenge experiments and two independent metastasis experiments.
Immunofluorescence
Immunofluorescence staining was performed as previously described (24). To determine percent CD4+ and CD8+ T cells in naive and immunized STAT4-/-, STAT6-/-, and BALB/c mice, splenocytes were double labeled for CD3 plus CD4 or CD3 plus CD8. Mice were immunized using the identical schedule and number of immunizations as the donors for effectors in the CTL assays; however, the cells were not from the same animals used in the CTL assays. Reported values for percent CD4+ and CD8+ T cells are averages from at least five animals per group.
CD4+ and CD8+ T cell depletions
Mice were in vivo depleted for CD4+ or
CD8+ T cells using mAbs to CD4 (GK1.5; Ref.
25) or CD8 (2.43; Ref. 26) on days -6, -3,
and -1, and one to two times a week thereafter, where day 0 is the day
of tumor challenge, as previously described (22). All mice
were checked by indirect immunofluorescence at the end of the
experiment (day 42) for completeness of depletions. In the experiments
shown in Figs. 2
and 3, CD4 and CD8 levels in depleted mice were <1%,
except for one of the CD4-depleted mice which had 8%
CD4+ T cells. For CTL assays, immunized donors
were depleted for CD4+ or
CD8+ T cells using mAbs to CD4 (GK1.5) or CD8
(2.43) before the last immunization using the same schedule as above,
where day 0 is the day of the final immunization and spleens were
removed on day 5. Data presented are representative of two independent
experiments.
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CTL assays were performed as previously described
(27) with the following modifications. Target cells (4T1
and melF10) were labeled at up to 107 cells/500
µl FCS with 100 µC 51Cr (NEN, Boston, MA) for
1.5 h at 37°C. Labeled cells were washed with excess PBS,
incubated an additional 30 min at 37°C, and used at 5 x
104 cells per well. For the CTL experiment of
Fig. 4, splenic effector cells were obtained from mice that were
immunized six times with 5000 rad irradiated 5 x
105 4T1/Ad/CD80
(24) plus 5 x 105 4T1/SEB
(23) cells. The first immunization was performed on day 1,
and subsequent immunizations on days 16, 28, 35, 49, and 62
(approximately every 2 wk). Spleens were removed 5 days after the last
immunization and used directly in the assays. Labeled targets were
incubated with the indicated number of effector cells in 96-well
round-bottom plates at 37°C for 
18 h. Percentage cytotoxicity
= [(cpm experimental - cpm spontaneous)/(cpm total - cpm
spontaneous)] x 100%. Net cytotoxicity is the percent cytotoxicity
of the specific targets (4T1) minus the percent cytotoxicity of the
irrelevant targets (B16 melF10). Data presented are representative of
two independent experiments. (For the second experiment, mice were
immunized five, instead of six, times.) An additional CTL experiment
was performed using splenocytes from BALB/c,
STAT4-/-, and STAT6-/-
mice immunized five times with wild-type 4T1 cells (same schedule and
number of immunizing cells as above.) Each CTL experiment was conducted
with splenic effectors from BALB/c, STAT4-/-,
and STAT6-/- mice that were immunized
concurrently using the identical immunization schedule and number of
immunizing cells. The effectors were assayed concurrently on the same
batch of target cells prepared for each experiment.
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A Student’s t test for unequal variances was performed using Microsoft Excel (Redmond, WA) to determine the statistical significance of indicated data.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The BALB/c-derived 4T1 mouse mammary carcinoma closely models
human breast cancer in that it grows progressively in the anatomically
correct site (mammary gland) and spontaneously metastasizes to a
variety of target organs (21, 24, 28, 29). 4T1 is highly
malignant in that as few as 7 x 103 cells
implanted into the mammary gland lead to progressively growing primary
and metastatic tumor in >95% of inoculated mice. 4T1 is also
nonimmunogenic in that immunization with irradiated 4T1 cells provides
no protection against wild-type tumor (23, 24). To assess
the effects of the STAT4 and STAT6 genes on tumor growth, female
BALB/c, STAT6-/-, and
STAT4-/- mice were inoculated in the mammary
gland with 4T1 tumor cells. As shown in Fig. 1, following inoculation of 7 x
103 4T1 cells, onset of primary tumor growth and
growth rate are slowed in STAT6-/- mice
relative to STAT4-/- or wild-type BALB/c mice.
Therefore, deletion of the STAT6 gene reduces primary mammary tumor
growth, suggesting that the presence of a functional STAT6 gene
facilitates tumor cell proliferation.
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Following inoculation into the mammary gland, 4T1 tumor cells
spontaneously metastasize to the lungs, liver, brain, lymph nodes,
blood, and bone marrow (21, 24, 29). The kinetics of
metastasis varies with the target organs; however, the earliest
metastases are found in the lymph nodes draining the site of primary
tumor growth and the lungs. Within 2–3 wk of inoculation into the
mammary gland, 95% of mice have metastatic cells in their lungs
(23, 24). Because 4T1 cells are 6-thioguanine resistant,
metastatic tumor burden in target organs can be accurately quantified
(24). To determine whether metastatic spread is affected
by the STAT4 and/or STAT6 genes, BALB/c,
STAT6-/-, and STAT4-/-
mice were inoculated in the mammary gland with 7 x
103 4T1 cells, mice were sacrificed 42 days
later, and the number of 4T1 cells in their lungs were measured. As
shown in Fig. 2
, metastatic cells in the
lungs of BALB/c mice range between 0 and 4 x
106 per mouse, while four of five
STAT4-/- mice have >2 x
104 cells each, and none of the
STAT6-/- mice have >103
metastatic cells. Therefore, STAT6-/- mice have
fewer metastatic cells in their lungs than either
STAT4-/- or wild-type BALB/c mice, suggesting
that expression of a functional STAT6 gene favors metastatic tumor
growth.
Reduced primary and metastatic tumor growth is mediated by CD8+ T cells and CD4+ T cells are not involved
To identify the effector cells responsible for the reduced tumor
burdens of STAT6-/- mice, mice were in vivo
depleted for CD4+ or CD8+ T
cells before tumor inoculation into the mammary gland. Depletions were
initiated on day -6 before tumor challenge and continued through day
42 of tumor growth. Primary tumor growth was measured throughout the
42-day period. As shown in Fig. 3, control untreated BALB/c and CD8-depleted
STAT6-/- mice have rapidly and progressively
growing primary mammary tumors, while CD4-depleted
STAT6-/- and control IgG-depleted
STAT6-/- mice have more slowly growing primary
tumors. CD4- and CD8-depleted STAT6-/- mice
were also followed for metastatic disease. Depletions were started on
day -6, mice were inoculated with 4T1 tumor in the mammary gland on
day 0, and depletions were continued until day 42 when the mice were
sacrificed and the number of clonogenic metastatic cells in the lungs
were quantified by the 6-TG assay. As shown in Fig. 2, STAT6-/- mice depleted of
CD8+ T cells have higher levels of metastatic
tumor cells than nondepleted STAT6-/- mice. In
contrast, CD4-depleted and control IgG-depleted
STAT6-/- mice have very low levels of
metastatic cells in the lungs, comparable to nondepleted
STAT6-/- mice. Therefore, depletion of
CD8+ T cells, but not CD4+
T cells in STAT6-/- mice, negates the
anti-tumor effect, indicating that CD8+ T
cells are critical for tumor rejection and that
CD4+ T cells are not involved.
Tumor-specific CD8+ CTL develop in STAT6-/- mice, but not in wild-type BALB/c mice
The results of Figs. 2 and 3 demonstrate that
CD8+ T cells are responsible for the reduced
primary tumor growth and metastases in STAT6-/-
mice. To determine whether the difference in tumor susceptibility
between STAT6-/-,
STAT4-/-, and BALB/c mice is due to
differential activation of CD8+ T cells, CTL
assays were performed using splenocytes from immunized mice and
51Cr-labeled 4T1 cells as specific targets and
B16 melF10 melanoma cells as irrelevant targets. In initial
experiments, BALB/c, STAT4-/-, and
STAT6-/- mice were immunized with irradiated
wild-type 4T1 cells. Only STAT6-/- effectors
had significant cytotoxic activity (net cytotoxicity of 0, 12, and 56%
for BALB/c, STAT4-/-, and
STAT6-/- effectors, respectively, at a ratio of
120:1).
For other studies, we have developed 4T1 cell-based vaccines as therapy
agents for the treatment of 4T1 tumors in wild-type BALB/c mice. The
vaccines consist of wild-type 4T1 cells transfected with syngeneic MHC
class II and CD80 genes (4T1/Ad/CD80)
(24) or Streptococcus aureus enterotoxin B gene
(4T1/SEB) (23). To determine whether
STAT6-/- mice respond selectively to the
vaccines, BALB/c, STAT4-/-, and
STAT6-/- mice were immunized with
4T1/Ad/CD80 plus 4T1/SEB cells, and CTL assays
were performed. As shown in Fig. 4, STAT6-/- mice have strong 4T1-specific CTL
activity, while effectors from STAT4-/- mice
have modest activity and BALB/c mice have minimal activity. Depletion
of CD8+, but not CD4+, T
cells from immunized STAT6-/- donors before
harvesting splenocytes for CTL assays, eliminates 4T1-specific
cytotoxicity, demonstrating that the CTL effect is
CD8+ T cell-mediated (data not shown).
The increased CTL activity in 4T1-immunized STAT6-/- mice may be due to differences in quantities of CD4+ and CD8+ T cells between BALB/c, STAT4-/-, and STAT6-/- mice. To test this possibility, splenocytes from naive and immunized BALB/c, STAT4-/-, and STAT6-/- mice were stained for CD3+CD4+ and CD3+CD8+ T cells and analyzed by flow cytometry. Percentages of CD4+ and CD8+ T cells in naive BALB/c, STAT4-/-, and STAT6-/- mice do not differ between the strains (CD4+ T cells in naive BALB/c, STAT4-/-, and STAT6-/- mice: 24.5, 29.3, and 26.9%, respectively; CD8+ T cells: 9.4, 9.3, and 7.8%, respectively). Likewise, the percentages of CD4+ and CD8+ T cells in immunized BALB/c, STAT4-/-, and STAT6-/- mice do not differ from those in naive mice (CD4+ T cells in immunized BALB/c, STAT4-/-, and STAT6-/- mice: 25.0, 28.2, and 25.8%, respectively; CD8+ T cells: 8.1, 8.9, and 9.4%, respectively). Therefore, the knockout mice do not have significantly more CD8+ T cells, and the increased tumor-specific CTL activity of STAT6-/- mice cannot be explained because of higher quantities of CD8+ cytotoxic cells.
Therefore, significant tumor-specific CD8+ CTL activity develops in STAT6-/- mice, but does not develop in BALB/c or STAT4-/- mice, even when the genetically modified tumor vaccines are the immunizing agent.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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If preferential development of tumor-specific Th1 cells is not responsible for enhanced tumor immunity in STAT6-/- mice, why does deletion of the STAT6 gene have such a profound effect on tumor growth? A trivial explanation is that the STAT6-/- mice are sufficiently genetically disparate from BALB/c mice that the 4T1 tumor is essentially an allograft and therefore immunogenic in STAT6-/- mice. This explanation is unlikely for at least two reasons. First, STAT6-/- mice have been backcrossed 10 generations to BALB/c mice, making them >99.99% BALB/c, and making it very unlikely that there are significant histocompatibility differences between 4T1 tumor cells and STAT6-/- mice. Second, because the STAT4-/- mice have been similarly backcrossed to BALB/c, if reduced tumor growth is due to genetic discrepancies, then STAT4-/- mice should also exhibit reduced tumor growth; however, their pattern of tumor progression is very similar to that of wild-type BALB/c mice.
Because CD4+ T cells are not obviously involved, deletion of the STAT6 gene must enhance tumor immunity via a mechanism independent of CD4+ T cells. There are several possible alternative mechanisms. First, STAT6-/- mice may preferentially produce Tc1 CD8+ T cells that are more efficacious than Tc2 cells in reducing tumor cell growth. Second, the STAT6 gene may be involved in a signaling pathway that produces an inhibitor that blocks CD8+ T cell-mediated anti-tumor immunity. Elimination of this inhibitor results in enhanced development of tumor-specific CD8+ T effector cells. Third, CD8+ T cells are one component of the enhanced anti-tumor effect, but other factors, such as anti-angiogenic factors, are also involved. Inactivation of the STAT6 gene favors the development of anti-angiogenic mechanisms that limit primary tumor and metastatic tumor growth. Therefore, STAT6-/- mice may show reduced tumor growth due to immunologic and nonimmunologic mechanisms.
In earlier studies, the 4T1 vaccines (4T1/Ad/CD80 plus 4T1/SEB) have shown significant therapeutic efficacy in wild-type BALB/c mice (23, 24), and in vivo CD8+ T cell depletion experiments have shown that the effect is at least partially due to CD8+ T cells. Therefore, it is surprising that the vaccines only stimulate a significant CD8+ T cell response in STAT6-/- mice, and not in BALB/c mice.
Regardless of the mechanism by which STAT6-/- mice have enhanced immunity, the reduction in primary tumor growth and metastatic disease is large and is unusual in that knocking out a gene results in a gain-of-function phenotype. This observation raises the possibility that inactivation of the STAT6-/- gene might enhance the development of tumor-specific immunity and facilitate tumor rejection and/or limit malignant cell proliferation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Suzanne Ostrand-Rosenberg, Department of Biology, University of Maryland, 1000 Hilltop Circle, Baltimore, MD 21250.
3 Abbreviations used in this paper: STAT6-/-, BALB/c mouse knocked out for the STAT6 gene; STAT4-/-, BALB/c mouse knocked out for the STAT4 gene; Tc1, CD8+ T cytotoxic 1 cells; Tc2, CD8+ T cytotoxic 2 cells; 4T1, BALB/c mouse mammary carcinoma.
Received for publication August 2, 2000. Accepted for publication September 26, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Cancer Immunol. Immunother. 49:34.[Medline]
2microglobulin-/- knockout mice contain low levels of CD8+ cytotoxic T lymphocytes that mediate specific tumor rejection. J. Immunol. 151:6283.[Abstract]
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