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*
Division of Clinical Immunology,
Department of Surgery, and
Immunobiology Center, Mount Sinai School of Medicine, New York, NY 10029
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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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(2) and
were defective in transducing signals following activation through the
TCR compared with T cells from control mice (6). These
signaling abnormalities resembled those associated with anergic T
cells, suggesting a mechanism for unresponsiveness (7, 8).
Taken together, our findings suggested the hypothesis that decreased
signal transduction by T cells in the tumor-bearing hosts might play a
role in their failure to mount an effective antitumor response. The early resection of progressively growing tumors has long been used as a mean of generating antitumor immunity (9), but the effect of resection at late time points after immune suppression has developed has not been studied. Since the loss of antitumor immunity correlated with tumor progression, we asked whether nonresponsiveness would be reversed by tumor resection. We observed that in the absence of the tumor all aspects of immune suppression reversed, resulting in a reduction in the elevated levels of Mac1+/Gr1+ cells in the spleen and an increase in the levels of signal transduction proteins needed for T cell activation. Most importantly, a population of T cells emerged that mediated protective immunity. These results suggested that the loss of antitumor immunity was not an irreversible event and that the presence of the tumor masked the existence of antitumor T cells. The implications of these conclusions for the immunotherapy of cancer are discussed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c mice were obtained from Charles River (Boston, MA). CMS5 is chemically induced fibrosarcoma of BALB/c origin (H-2d) (10). For in vivo inoculation, 0.5 x 106 freshly prepared tumor cells were injected s.c. in the back. In these experiments, groups contained three to five mice. Tumor growth was measured in millimeters as a mean diameter (longest surface length (a) and width (b), (a + b)/2). CMS4 is a chemically induced fibrosarcoma that is antigenically distinct from CMS5 (11). EL-4 is a thymoma of the H-2b haplotype used as a specificity control in cytotoxicity experiments. YAC-1 is MHC negative and is the prototypic target for NK cells.
mAbs and flow cytometry
For phenotypic analysis, spleen cells pooled from mice (five mice per group) were reacted with 100 ng of fluoresceinated anti-CD3 (145-2C11, hamster IgG; PharMingen, San Diego, CA), anti-Gr1 (rat, IgG2b; PharMingen), or anti-Mac1 (rat, IgG2b; PharMingen). Irrelevant isotype-matched Abs were used as controls. Cells were reacted with the desired Ab for 30 min at 4°C. Samples were washed twice in FACS buffer (PBS with 3% FBS and 0.02% sodium azide). Samples were analyzed for fluorescence using a Coulter Profile II flow cytometer (Palo Alto, CA), following gating on the lymphocyte population for analysis of CD3+ cells and on the nonlymphocyte population for the analysis of Mac1+ and Gr1+ cells.
For in vivo depletion studies, five mice per group were inoculated i.p. twice per week with 100 µl of anti-CD4 ascites (GK 1.5 rat IgG2b; Harlan Bioproducts for Science, Madison, WI), with 100 µl of anti-CD8 ascites (2.43, rat IgG2b), with both, or with 100 µl of an IgG2b isotype control. The completeness of the depletion was tested via FACS analysis and was always greater than 99% for the appropriate subset; the level of the other subset was unaffected.
For in vitro T cell enrichment, cells were prepared from spleens pooled from mice (five mice per group) by negative depletion of non-T cells with mAbs against I-Ad (MKD6) and the anti-heat stable Ag (J11d) (12, 13) and complement. An aliquot of cells was reacted with anti-CD3 mAb and analyzed via flow cytometry to assess the enrichment obtained. In general, greater than 85% of the cells expressed the T cell marker.
Western blotting
Cells were washed and lysed in buffer composed of 20 mM Tris (pH 8), 150 mM NaCl, 1% Nonidet P-40, 200 µM EDTA, 10 mM sodium pyrophosphate, and 100 mM sodium fluoride containing the protease inhibitors PMSF, iodoacetamide, leupeptin, aprotinin, and sodium vanadate. Lysates corresponding to 4 x 106 enriched T cells/sample were separated on a 10% SDS-PAGE gel at 200 V for 45 min. Material was electroblotted to polyvinylidene difluoride membrane, blocked with 5% BSA, and immunoblotted with a rabbit anti-lck antiserum (Santa Cruz Biotechnology, Santa Cruz, CA). The filter then was reacted with a secondary Ab conjugated with HRP and developed via enhanced chemiluminescence (DuPont-NEN, Boston, MA).
Generation of CTL and the cell-mediated lympholysis assay
To prepare CTL, single cell suspensions of spleen cells devoid of erythrocytes were prepared and resuspended at 2 x 106/ml in RPMI medium (BioWhittaker, Walkersville, MD) supplemented with 10% FBS, penicillin (100 U/ml), streptomycin (100 µg/ml), 2 mM L-glutamine, 25 mM HEPES buffer, 5 x 10-5 2-ME, 1 mM sodium pyruvate, and 0.1 mM nonessential amino acids. These responder cells were stimulated for 6 days at a 10:1 ratio with x-irradiated CMS5 cells (6000 rad). For these studies, CD8- T cell effectors were obtained by negative depletion with the anti-CD8 mAb 2.43 (rat IgG2b) and complement. Briefly, cells were resuspended at 107/ml and incubated with the mAb or with PBS, as a control, for 30 min at 4°C. After washing the cells, they were incubated twice at 37°C with a 1/10 dilution of baby rabbit complement (Pel-Freeze; Clinical System Division, Brown Deer, WI). At the end of the procedure, cells were resuspended in the original starting volume (13). For labeling, target cells were cultured for 1.5 h at 37°C in 6% CO2 in the presence of 150 µCi of 51Cr sodium chromate (DuPont-NEN). Cells were washed twice and counted, and 10,000 cells were distributed per well. Targets and effectors were mixed at several E:T ratios. After 18 h of incubation, supernatants were harvested from each well. Percent specific lysis was calculated as: [(cpm experimental cultures - cpm spontaneous release)/(cpm maximum release - cpm spontaneous release)] x 100.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The absence of antitumor responsiveness by T cells in vivo, as
well as their reduced levels of signaling proteins in vitro, have been
associated with the presence of elevated numbers of
Mac1+ and/or Gr1+ cells in
the spleen (4, 14, 15, 16, 17, 18). To determine the phenotype of
cells in the spleens following tumor resection, mice were inoculated
s.c. with CMS5 tumor cells. After 28 days, tumors were resected.
Spleens were harvested 2, 5, and 10 days later and analyzed for the
presence of CD3+, Mac1+,
and Gr1+ cells using flow cytometry. Similar to
other investigators (4, 14, 15, 19), we observed that on
day 28, before tumor resection, spleens of the naive mice contained
elevated numbers of nonlymphocytes compared with those of tumor-bearing
mice (Fig. 1
, a and
b). Furthermore, decreased levels of
CD3+ cells and increased levels of
Mac1+ Gr1+ cells were seen
in tumor-bearing compared with naive controls (Fig. 1, c–f). In this figure, the absolute percentage of positive
cells in the spleen (above the bars and underlined in the figure) was
determined by multiplying the percentage of positive cells within the
gate by the percentage of total splenocytes within the gate. The
absolute numbers of cells (x103) of the
particular phenotype observed in the spleen are given by the numbers
directly above the bars. These were determined by multiplying the
absolute percentage of positive cells by the total cell number.
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a) (20).
Interestingly, in the tumor-bearing host, the majority of
Gr1+ cells stained brightly for Gr1
(Gr1high), with very few
Gr1low cells (Fig. 2b). A subsequent
experiment using two-color flow cytometry demonstrated that all of the
Gr1+ cells were contained within the
Mac1+ population, but that some
Mac1+ cells were Gr1-
(results not shown). Levels of B cells, determined by staining with the
anti-CD45 mAb B220, were normal (results not shown). Surprisingly,
within 48 h of tumor resection, we observed a dramatic change in
the phenotype of cells within the spleen (Fig. 1
, c–f).
Specifically, levels of CD3+ and
Gr1low cells began to increase, while those of
Mac1+ and Gr1high began to
decrease. Such changes could be seen as early as 24 h (results not
shown). By day 10, all values were similar to those seen in
mock-resected mice.
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We have previously reported that one of the abnormalities in
tumor-bearing hosts associated with their weak T cell responses is the
diminished levels of signal transduction proteins, such as
p56lck, p59fyn, and the
CD3/TCR -chain (2). These abnormalities, however, were
not observed in immune animals, whose levels of these proteins were
similar to those of naive animals. Other investigators reported that
following in vitro culture of T cells from tumor-bearing mice, levels
of CD3/TCR reverted to normal (21). Whether protein
levels can normalize in vivo, however, has not been tested. To examine
whether levels of p56lck were influenced by
tumor resection, mice were inoculated with CMS5 cells and after 28 days
their tumors were resected. The mean size of the tumors, calculated as
longest surface length (a) and width (b),
(a + b)/2, was 18 ± 5 mm. Control mice
underwent mock resection. On days 2 and 10 after resection, spleens
were pooled from each group and T cells isolated by negative selection
of T cells with mAbs against I-Ad (MKD6), the
anti-heat stable Ag (J11d), and complement.
Using Western blotting, we observed that while T cells from unresected
mice had the expected decreased levels of p56lck
compared with control mice, following tumor resection levels of this
protein begin to increase gradually. By day 10, levels of
p56lck were indistinguishable from those in
mock-resected mice (Fig. 3). Although it
is formally possible that the increase in p56lck
was due to the death of the abnormal T cells and an influx of normal T
cells, the rapidity with which the response was observed suggests that
levels of p56lck might have been restored in
those cells in which they had been decreased.
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The normalization of the cellular composition of the spleen and
the increased levels in signal transduction proteins would be
biologically significant only if they influenced antitumor immunity. To
test this, tumors were resected from mice 28 days after the inoculation
of tumor cells. Ten days later, the mice were challenged with an s.c.
inoculum of CMS5 or with CMS4, a tumor antigenically unrelated to CMS5.
Fig. 4 shows that CMS5 cells grew rapidly
in naive mice, while by 31 days no tumors had developed in resected
mice. The antitumor response was specific, because resected mice failed
to reject the challenge of CMS4 cells. Furthermore, rejection depended
upon the presence of T cells, because resected mice that were depleted
of CD4+ and CD8+ T cells
did not reject the challenge (Fig. 5).
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To determine the phenotype of the effector cell, tumor-bearing
mice were resected, and on day 10, after immunity was restored,
depleted for either CD4+ or
CD8+ T cells. A group of mice was treated with an
isotype control Ab. All mice were challenged with CMS5 cells and tumor
growth followed with time. We observed that none of the mice depleted
for CD4+ or CD8+ cells was
able to reject the tumor challenge (Fig. 6). In other experiments, from a total of
10 mice depleted for CD4+ cells, none was able to
reject the challenge, and only 2 of 10 mice depleted for
CD8+ cells were. These results, together with
those of others, indicated that CD8+ T cells are
necessary, but not sufficient to reject the challenge, suggesting that
CD4+ cells play a very important role
(22).
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To test whether protection against tumor challenge could be
adoptively transferred to naive mice, naive and resected mice were
inoculated with 0.5 x 106 CMS5 tumor cells.
After 28 days, resected-immune or tumor-bearing mice were sacrificed,
their spleens harvested, and the single cell suspensions enriched for T
cells by negative depletion of non-T cells. Naive recipient mice were
injected i.v. with 30 x 106 T cells from
tumor-bearing, from resected-immune mice, or with saline as a control.
Twenty-four hours later, all mice received an s.c. challenge of CMS5
tumor cells. We observed that tumors developed in mice that received no
cells or T cells from tumor-bearing mice, while mice that received the
T cells from resected-immune mice were protected against tumor growth.
Thus, protection against tumor challenge was transferable (Fig. 7).
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). We observed that even
when mice were challenged 3 wk after the adoptive transfer, tumors
developed. This experiment suggested that protection to a tumor
challenge is not conferred simply by transferring enriched T cells
depleted for Gr1+/Mac1+
cells from a tumor-bearing donor to a naive host. These results are
consistent with the interpretation that APC loaded with tumor peptides
may be necessary to restore antitumor responses by T cells.
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It is increasingly appreciated that in several systems, including
ours, tumor-specific CTL are demonstrable early after tumor cell
inoculation, but that they disappear with time (5, 13, 23). In previous studies, we observed that immunization with
IL-2-secreting tumor cells induced a strong antitumor response in naive
mice mediated largely by T cells (5, 13) and that the loss
of in vitro CD8+ CTL activity was associated with
the failure of the mice to reject a challenge of viable tumor cells in
vivo (5). To test whether tumor resection had restored
CD8+ CTL function, resected mice were challenged
with CMS5 tumor cells. After 8 wk,
spleens were harvested from both groups and restimulated in vitro with
x-irradiated CMS5 tumor cells. Six days later, before
testing for cytotoxicity, an aliquot of effector cells was treated with
anti-CD8 Ab plus complement or with complement alone. Our results
showed that CTL able to lyse specific tumor cells were detectable in
cultures of splenocytes from mice challenged with CMS5 tumor cells
(Fig. 9). No lysis of EL-4, an irrelevant target, or YAC-1, an NK
target, was seen, consistent with the development of a response that
was Ag specific, T cell mediated, and dependent upon the presence of
CD8+ T cells. In contrast, anti-CD8 treatment
markedly reduced this cytotoxic activity. Taken together, these results
suggested that tumor-bearing mice contained a population of long-lived
antitumor T cells that was unmasked without any further immunization in
the absence of the tumor.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We and others have reported that there is a loss of signal transduction
ability by T cells in tumor-bearing hosts (1, 2, 6). In a
variety of systems, the infiltration of granulocytes in the spleen has
been observed (4, 14, 15, 16) (Figs. 1 and 2). Saito’s group
reported that these cells could induce the loss of CD3 as well as
prevent Ag-specific T cell proliferation in vitro (15, 16). Of greatest interest to us are the mechanisms responsible
for the failure to sustain an antitumor response after it has been
initiated. T cells from late tumor-bearing mice lose the ability to
differentiate into CTL following immunization with virus in vivo, to
proliferate in response to stimulation with Ag in vitro (6, 13), or to secrete IL-2 in vitro after cross-linking the TCR
(35). Although progress in understanding the signals
required by T cells for activation has led to the rational design of
immunotherapeutic approaches to stimulate the development of T
cell-mediated antitumor immunity, the effectiveness of such vaccines
might be compromised in tumor-bearing hosts that are unable to develop
immunity even to viruses that elicit strong T cell responses
(6). Nevertheless, patients with advanced disease
often have exhausted other forms of therapy. Thus, the ability to
reverse immune suppression is an important goal that requires an
understanding of the regulation of T cell unresponsiveness.
In these studies, we identified several immunological abnormalities
that were reversed by tumor resection. First, the levels of the
Gr1+ and Mac1+ cells in the
spleen were normalized (Fig. 2). The Gr1low
population of cells that was largely absent in the day 28 tumor-bearing
mouse increased and the cells in the Gr1high
population decreased. High expression of Gr1 is found on mature
granulocytes, while, at least in the bone marrow, cells expressing low
levels of Gr1 are immature progenitors and myelocytes
(36, 37, 38). While
Mac1+/Gr1+ cells have been
shown to induce suppression (17, 18), we are not aware of
other reports describing Gr1high and
Gr1low cells in the spleen. Whether they
represent different stages of differentiation of one cell or distinct
subsets is currently under investigation. It is of interest that in
some systems, T cell-mediated rejection of tumors genetically
engineered to secrete G-CSF and/or IL-2 requires the infiltration of
Gr1+ cells into the tumor (37, 38).
These investigators did not examine whether they were found in the
spleens of the immune mice. Second, we demonstrated normalization of
the levels of p56lck in T cells following tumor
resection (Fig. 3). Third and most important from a biological
perspective, following tumor resection, formerly immune suppressed mice
specifically rejected a challenge of CMS5 tumor cells without any
further immunization (Fig. 4). The mechanism involved both
CD4+ and CD8+ cells,
because mice depleted for CD4+ cells failed to
reject their tumors, and mice depleted for CD8+
cells also failed to reject their tumors (Fig. 6). Interestingly,
adoptive transfer of enriched splenic T cells from tumor-bearing mice
did not restore T cell responsiveness, even if the hosts were
challenged with tumor cells as late as 21 days after adoptive transfer.
These results suggest the hypothesis that professional APC loaded with
tumor peptides may be required to obtain antitumor responses.
Our working hypothesis is that cytokines released by
CD4+ cells play an important role in tumor
rejection, consistent with results of other groups. For example, the
depletion of CD4+ cells in already immune mice,
before tumor challenge, prevents tumor rejection (39). In
addition, following vaccination with an irradiated MHC class
I- tumor vaccine, the rejection of class
I- tumor cells requires
CD4+ cells, possibly to recruit APC or activate
NK cells (40). Finally, it is increasingly appreciated
that CD4+ cells can produce cytokines such as the
Th1 IFN-
and/or the Th2 IL-4 cytokines that then can recruit a
variety of other effector cells, e.g., eosinophils, macrophages, to the
tumor (22). The mechanism by which the tumor induces T
cell suppression is unknown, but in our system it does not involve the
secretion of a soluble cytokine that directly inhibits T cells
(13). Also unclear is the relationship, if any, between
the decrease in the Gr1high population, the
return of p56lck, and the emergence of
protective immunity. Answers to these questions await the results of
further experimentation.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Karen Zier, Mount Sinai School of Medicine, Box 1089, 1425 Madison Avenue, New York, NY 10029. E-mail address:
Received for publication August 31, 1998. Accepted for publication December 3, 1999.
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