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Departments of
* Cancer Biology,
Biometrics, and
Hybridoma, Immunex Research and Development, Seattle, WA 98101
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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- and
CD40-mediated signals were also required, because no benefit was
observed on treatment with 4-1BB mAb in mice in which the genes for
these molecules had been knocked out. Interestingly, 4-1BB-mediated
stimulation of immune responses in CD40L-/- mice is
effective (although at a reduced level), and may suggest the existence
of an alternative ligand for CD40. Additional experiments in
IL-15-/- mice indicate that IL-15 is not required for
either the generation of the primary tumor-specific immune response or
the maintenance of the memory immune response. In contrast, the
presence of CD4 cells during the primary immune response appears to
play a significant role in the maintenance of effective antitumor
memory. Finally, in mice in which the number of dendritic cells had
been expanded by Fms-like tyrosine kinase3 ligand treatment, the
antitumor effects of 4-1BB ligation were
enhanced. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Studies in a variety of systems have demonstrated that engagement of
the TCR alone is not sufficient for full T cell activation, expansion,
and cytokine secretion. Additional costimulatory signals are also
required, of which the signal delivered by B7 molecules on APCs to CD28
on the T cell is the most widely characterized (12, 13, 14). T
cells typically receive this costimulatory signal while they are
exposed to Ags in the context of MHC by APCs (12, 15, 16, 17).
Failure to receive a second signal can lead to anergy or apoptosis
(18, 19, 20, 21, 22). One approach to increase the costimulation of T
cells in tumor-bearing mice has been to block or neutralize CTLA-4 (a
naturally occurring inhibitor of CD28/B7 interactions), thereby
increasing the CD28/B7 interaction (9, 10, 23, 24, 25).
Alternatively, tumor cells have been directly transfected with B7
family members in an effort to promote their ability to act directly as
APC (13, 26, 27). Other strategies include expansion and
activation of specific subsets of "professional" APCs (i.e.,
dendritic cells (DC)2
in vivo by treatments of Fms-like tyrosine kinase3 ligand (Flt3L)
either alone or in combination with CD40 ligand (CD40L), transfection
of tumors with cytokines such as GM-CSF, and ex vivo expansion and Ag
loading of DC with defined tumor Ags (7, 28, 29, 30, 31). These
strategies have in common the goal of increasing APC function by
increasing the number of available APC and/or enhancing the
Ag-presenting function of the APC. Reciprocal approaches (e.g.,
enhancing the receptivity of the T cell to signals from the APC or the
ability of T cells to proliferate in response to Ag using cytokines
such as IL-2, IFN-, etc.) have also been tried but have met with
only limited success (32, 33). This may be due, in part,
to the extremely short half-life and lack of selectivity of these
cytokines in vivo.
An alternative approach is to specifically target activated subpopulations of T cells with appropriate costimulatory signals. In this regard, 4-1BB, a member of the TNFR superfamily, represents an attractive potential target. It is expressed on activated, but not resting, CD4 and CD8 T cells, and ligation of this receptor by either its ligand or agonistic Abs has been shown to provide a potent costimulatory signal (34, 35). The costimulatory signal has been shown to be more potent for CD8 T cells than CD4 T cells (35, 36).
Previous studies have shown that administration of agonistic 4-1BB Abs or 4-1BB ligand gene expression by tumors can lead to generation of effective antitumor responses (37, 38, 39, 40). Interestingly, preliminary results from our own studies were at odds with those of others that indicated that both CD4 and NK cells were absolutely required for the generation of effective tumor immune responses in vivo by agonistic 4-1BB mAb (39). Thus, the studies reported here were undertaken to more fully characterize the cellular and cytokine requirements for the enhancement of tumor immune responses mediated by ligation of 4-1BB.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female C57BL/10J,
C57BL/6Ncr-TNFrsf5tm1Kik
(CD40-/-) and
C57BL/6-Ifngtm1Ts
(IFN--/-) mice were purchased from The
Jackson Laboratory (Bar Harbor, ME). Female (C57BL/6 x
DBA/2)F1 (B6D2F1), C57BL/6,
and C57BL/6 Abb/B2 (MHC class II-/-) mice were
purchased from Taconic Farms (Germantown, NY).
CD40L-/- and IL-15-/-
mice were generated at Immunex (Seattle, WA) by homologous gene
disruption (41). All mice were age matched at the
beginning of each experiment (8–12 wk of age) and kept under specific
pathogen-free conditions at Immunex.
Tumor cell lines
The B10.2 fibrosarcoma is a methylcholanthrene-induced tumor of C57BL/10 origin, and the 87 fibrosarcoma is a UVB-induced tumor of C3H/HeN (MTV-) origin. P815 mastocytoma and B16-F0 melanoma were purchased from American Type Culture Collection (ATCC; Manassas, VA). K1735 melanoma was a gift from Dr. M. Kripke (University of Texas M. D. Anderson Medical Center, Houston, TX). RENCA renal cell carcinoma was a gift from Dr. C. Tannenbaum (Cleveland Clinic Foundation, Cleveland, OH). Tumor inoculations were performed by s.c. injection of mice via the midline ventral abdomen in a total volume of 50 µl. Tumors were measured weekly with calipers; tumor size represents the product of two perpendicular diameters and is expressed as the average of only those mice bearing tumors within each treatment group.
Abs and cytokines
Anti-4-1BB (M6, rat IgG2a) and anti-CD40L (M158, rat IgG2b) mAb were produced and purified at Immunex. Flt3L was produced at Immunex as described previously (28). Purified rat IgG and mouse serum albumin (MSA) were purchased from Sigma-Aldrich (St. Louis, MO). Depleting antiCD4 (GK1.5, rat IgG2b), anti -CD8 (2.43, rat IgG2b) and anti-NK1.1 (PK136, mouse IgG2a) were purified from culture supernatants of hybridoma lines purchased from ATCC. Asialo-GM1 antiserum was purchased from Wako Pure Chemical Industries (Osaka, Japan) and used in accordance with the manufacturer’s recommendations.
Statistics
Biostatistical evaluation of tumor rejection frequencies was conducted by analysis of combined results from multiple independent experiments using Fisher’s exact test. All tests were two-sided and a nominal p value of 0.05 was used to determine statistical significance.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous studies have demonstrated that treatment of tumor-bearing
mice with certain mAb specific for murine 4-1BB could promote the
generation of effective tumor immunity in vivo (38). To
test whether a 4-1BB mAb produced at Immunex (4-1BB (M6)) could
similarly act to induce tumor rejection, C57BL/10 mice were injected
s.c. with B10.2 fibrosarcoma cells and subsequently treated with two
100-µg i.p. injections of 4-1BB (M6) at various times post-tumor
challenge. Fig. 1
shows the results from
two experiments in which mice were treated beginning as early as 3
days, or as late as 24 days, after tumor implantation. Treatments at
all time points resulted in complete tumor rejection in a high
proportion of mice and significant reduction in tumor size and growth
rates in the remainder. Treatment of well-established B10.2 tumors
beginning as late as day 24 post-tumor challenge resulted in complete
tumor rejection of tumors in up to 80% of the
tumor-bearingmice. Tumor rejection induced by treatment with
4-1BB (M6) was mediated by CD8+ T cells and
resulted in the generation of long-lasting tumor-specific memory (data
not shown).
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). The two tumors
not affected by the 4-1BB (M6) treatment (K1735 and B16-F0) were MHC
class I negative by flow cytometry (data not shown).
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Depletion of CD8 T cells in mice before initiating treatment with
4-1BB(M6) mAb completely abrogated tumor rejection of the B10.2
fibrosarcoma in C57B10 mice (Fig. 2). In
contrast, depletion of NK cells with either anti-NK1.1 or
asialo-GM1 had no effect on rejection of the B10.2 tumors, and neither
did depletion of CD4 cells with GK1.5. These results contrast with
initial studies reported by Melero et al. (38, 39).
Potential differences in results due to the use of different tumors
(B10.2 vs P815) in different strains of mice (C57BL/10 vs
B6D2F1) were ruled out in a separate experiment
in which B6D2F1 mice were depleted of NK, CD4, or
CD8 cells using Abs described above; challenged with P815 tumor cells;
and treated with 4-1BB (M6) mAb beginning on day 5. Again only CD8
cells were required for tumor rejection subsequent to treatment with
4-1BB(M6) mAb (data not shown). In additional studies by Melero et al.
(42) in which P815 cells were transformed to express 4-1BB
ligand, the CD4 requirement was lost.
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The majority of mice that rejected their initial tumor challenge
subsequent to 4-1BB (M6) treatment also rejected the tumor on
rechallenge 3 mo later. In mice that had been depleted of NK cells
before initial tumor challenge by treatment with either asialo-GM1- or
NK1.1-specific mAb, the rate of rejection of the secondary tumor
challenge proceeded at a rate and frequency (100%) comparable with
those observed in the positive control (i.e., tumor-immune) group.
However, the rate and frequency of rejection of the secondary tumor
challenge in mice that had been depleted of CD4 T cells during the
primary immune response were decreased compared with the other
treatment groups (Fig. 3). These data
suggest that although CD4 T cells are not required to generate an
effective primary effector response to tumors in vivo, they may play an
important role in the generation and/or maintenance of memory effector
cells.
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-/- mice
To further investigate the requirements for either CD4 or NK cells
in the generation of tumor-immune responses induced by 4-1BB mAb
treatment, we used MHC class II gene knockout mice that lacked
functional CD4 T cell activity and IL-15 knockout mice, which are
deficient in NK cells. Class II-/- mice lacking
Ag-specific CD4 T cell function were challenged with the B10.2 tumor
cells followed by treatment with 4-1BB (M6). Although these mice
were capable of rejecting the primary tumor challenge after 4-1BB (M6)
mAb treatment (Fig. 4A), they
exhibited a reduction in memory function similar to that seen in
the CD4-depleted mice (Fig. 4B).
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A). Rechallenge of both
wild-type and IL-15-/- mice that had
successfully rejected the initial tumor implants 3 mo earlier led to
tumor rejection with essentially identical kinetics, indicating that
IL-15 is not required for maintenance of tumor-reactive memory cells in
vivo (Fig. 5B).
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-/- mice
to reject B10.2 tumors with or without 4-1BB (M6) treatment. None of
the IFN--/- mice rejected the tumor
regardless of 4-1BB (M6) treatment, and the tumors grew more rapidly in
the IFN--/- than in the wild-type
tumor-bearing animals (Fig. 6). These
data indicate that IFN- is absolutely required for the generation of
effective tumor-immune responses in vivo and that this requirement is
not alleviated by treatment with 4-1BB specific mAb.
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Two approaches were used to determine whether CD40-CD40L
interactions were required for 4-1BB (M6)-enhanced tumor rejection. The
first experiments were conducted with anti-CD40L neutralizing Abs.
Administration of anit-CD40L (M158) was initiated on the day of tumor
challenge (day 0) and continued throughout the period of treatment with
anti-4-1BB (M6). Treatment of tumor-bearing mice with 4-1BB (M6)
mAb alone resulted in complete tumor rejection in 90% of the mice.
However, in the presence of CD40L, blockade treatment with 4-1BB (M6)
mAb resulted in only 10% tumor rejection (Fig. 7A). In the second approach,
we used mice in which either CD40 or CD40L had been selectively
disrupted. These mice were challenged with the B10.2 fibrosarcoma and
treated with 4-1BB (M6) mAb. Mice deficient in CD40 failed to reject
the tumor challenge. In contrast, mice deficient in CD40L were able to
reject the B10.2 tumor challenge, albeit at a slightly reduced rate
compared with 4-1BB (M6)-treated wild-type mice (Fig. 7B).
These data may suggest the existence of a second ligand for CD40 that
becomes induced in mice on which immune systems develop in the absence
of the primary ligand for CD40.
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DCs are potent stimulators in the primary activation of T cells.
Recent studies have demonstrated that expansion of DCs in vivo by
treatment with Flt3L is also capable of augmenting the generation of T
cell-mediated immune responses to tumors (28). In
addition, the combination of Flt3L with another costimulatory TNF
family member (CD40L) yields cooperative effects (29). To
determine whether combined treatments of Flt3L and 4-1BB (M6) would
result in enhanced tumor rejection, C57BL/10 mice were implanted with
the B10.2 tumor and treated with a suboptimal regimen of Flt3L (days
1–14) and/or injected with 41BB (M6) mAb on days 13 and 16. Treatment
with either Flt3L or 4-1BB (M6) resulted in tumor rejection in a
proportion of mice (40 and 80%, respectively), but combining Flt3L and
4-1BB (M6) treatments resulted in rejection of tumors in 100% of the
test mice and at a faster rate than in mice treated with either agent
alone (Fig. 8A). In a
follow-up experiment, tumors were implanted 10 days before initiating
treatment with a more aggressive regimen of Flt3L (20 injections on
days 11–30). Injections of 4-1BB (M6) were given on days 24 and 27.
Although administration of Flt3L or 4-1BB (M6) alone were effective
(resulting in 7 of 10 and 7 of 9 tumor rejections, respectively), the
combination resulted in complete tumor rejection in all 10 test mice
(Fig. 8B). In both settings, the sizes of tumors in the
remaining mice that had been treated with Flt3L or 4-1BB (M6) were
smaller than those in the control groups.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Initial studies in which mice were treated with 4-1BB (M6) mAb at
various times after tumor implantation demonstrated not only that this
mAb was capable of promoting the generation of effective immune
responses to the tumor but also that initiation of treatment relatively
soon after tumor challenge was not as effective as initiation of
treatment after the tumor had become more established (Fig. 1
). This
observation suggests that the mAb is acting on cells that have already
been activated by tumor Ags in vivo. Studies presented by Gramaglia et
al. (36) demonstrated peak expression of 4-1BB on
OVA-specific transgenic CD8 T cells at 48–72 h after stimulation in
vitro. In an in vivo setting, Takahashi et al. (46)
observed a relatively rapid and transient stimulation of 4-1BB
expression on a polyclonal T cells subsequent to immunization with the
superantigen staphylococcal enterotoxin A, with maximal
responses occurring at 12 h. In both of these settings, the
stimulatory signal(s) were very strong and relatively short-lived. In
the tumor settings used here, in which the precursor frequencies of
responding T cells are undoubtedly quite low, we have not been
able to detect significant increases in 4-1BB expression on polyclonal
CD8 cells. However, the fact that effective tumor-immune responses can
be stimulated in populations of CD8 cells contained in mice as early as
3–6 days and as late as 21–24 days after tumor implantation by
4-1BB-specific mAb indicates the continued functional expression of
this important TNFR superfamily member most likely as a result of
continued antigenic stimulation by a progressively growing tumor.
Further analysis of the cellular interactions demonstrated that while
CD8+ T cells were absolutely required,
CD4+ T cells, NK cells, and NKT cells were
not (Fig. 2) and is in sharp contrast to previously published results
by others (38, 39). The reason (s) for the difference in
results presented here compared with those obtained by others is not
immediately apparent. The possibility that the treatment protocols we
used for depletion of these subsets of cells were ineffective seems
highly unlikely because flow cytometric analysis of peripheral blood
from the treated mice demonstrated complete depletion of the relevant
subsets of cells (Fig. 2), and similar evaluation of secondary lymphoid
tissues resulted in identical results (data not shown). In addition,
genetic approaches using mice deficient in CD4 cells (class
II-/- mice) or NK cells
(IL-15-/- mice) showed concordant results
(summarized in Table II). The conclusion
that the 4-1BB-specific mAb is acting directly on
CD8+ T cells, and independent of CD4 T cell
function, is also bolstered by the fact that Ag-specific expansion of
OT-1 T cells is substantially augmented by treatment with 4-1BB (M6)
mAb (T. de Smedt, unpublished observations). Finally, in a
follow-up study, Melero et al. (42) have also reported
generation of tumor-immune responses to be CD4 independent.
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and 4A) but do appear to play a role in either the generation or
long term maintenance of memory responses (Figs. 3 and 4B).
In contrast to expectations based on results of others who have
reported a role for IL-15 in the clonal expansion of
CD8+ T cells with a memory phenotype
(47), this cytokine does not appear to be required for the
maintenance of such cells at a functional level at least for a time
period of up to 3 mo (Fig. 5). Interestingly, recent investigations by
Schluns et al. (48) and Goldrath et al. (49)
indicate that IL-7 is required for the generation and survival of
memory CD8 T cells where as IL-15 is required for basal homeostatic
proliferation of memory OVA-specific CD8+ T cells
(OT-1 cells). They also showed that although CD8 memory T cells had not
proliferated in the absence of IL-15, they were present at higher
numbers than in normal mice. They attributed this to less competition
among memory cells in IL-15-/- mice. However
they stated that although IL-15 was not required for the generation of
memory cells in the short term, (i.e., 3 mo), their results did
indicate IL-15 is required for long term (18 mo) survival. Clearly,
additional studies to evaluate and enumerate memory CD8 T cells induced
following stimulation of an immune response with 4-1BB mAb are
warranted.
Studies performed using cytokine and cytokine receptor knockout mice
also yielded additional information of interest. Not unexpectedly, mice
that were deficient in their ability to produce IFN- were unable to
develop effective immune responses to tumors even after treatment with
4-1BB (M6) mAb (Fig. 6). Whether this is due to failure of clonal
expansion of the tumor-reactive T cells, a failure of such cells to
differentiate into functional effector cells or the inability of
effector cells to traffic to the tumor site is unknown, although
results of studies presented by Nakajima et al. (50)
suggest the latter. However, studies evaluating the role of CD40 and
CD40L yielded a couple of surprises. First, studies using a
CD40L-specific mAb (M158) that blocks binding of this cytokine to its
receptor effectively inhibited the generation of tumor immunity
mediated by 4-1BB (M6) (Fig. 7A). Similar result were
obtained with CD40-/- mice. Coupled with the
fact that CD4 T cells are not required to develop 4-1BB-mediated effect
or cell responses, the data indicate that CD40L-CD40 interactions
between CD8 T cells and DC are critically required for T cell expansion
and function. Surprisingly, tumor-bearing
CD40L-/- mice were able to develop immune
responses to tumors when treated with 4-1BB (M6) mAb (Fig. 7B, and summarized in Table III).
Evaluation of composite results from four separate experiments
demonstrated that although the frequency of 4-1BB (M6)-induced tumor
rejection in CD40L-/-mice (37%) was somewhat
reduced when compared with wild-type mice (67%; p =
0.024), it was clearly greater than with untreated wild-type mice (0%;
p 0.0001) or 4-1BB (M6)-treated
CD40-/- mice (6%; p = 0.0307).
It was also greater than that observed in anti-CD40L (M158)-treated
mice (10%; p = 0.0467). Collectively, these data
suggest that there may be a second ligand for CD40 (CD40L.2?) the
function (perhaps even expression) of which is observed only when the
primary ligand (CD154) is not functionally expressed during the
development of the immune system. Clearly, acute blockade of function
(such as mediated by treatment with CD40L-specific mAb) is not
sufficient to promote expression and/or function of the putative
alternate ligand for CD40. The functional signal must also be
delivered via CD40 because 4-1BB (M6) treatment of
CD40-/- mice did not result in any detectable
benefit as judged by either tumor incidence or growth rate (Fig. 7B).
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In conclusion, our studies confirm the observation that agonistic mAb
to 4-1BB can promote the generation of effective CD8-mediated immune
responses to established tumors in vivo (38) and
substantially expand our knowledge of the cellular and cytokine
interactions involved in and required for this effect. At the cellular
level, interactions between DCs and CD8 T cells appear to be necessary
and sufficient to promote priming and activation of T cells to a point
at which costimulation through 4-1BB is effective in generating tumor
immunity. Interestingly, although CD4 T cells are not required for
4-1BB-mediated augmentation of tumor immunity, they do appear to play a
role in the maintenance of functional memory immune responses. The data
also indicate that a CD40-mediated signal is required for clonal
expansion and differentiation of effector cell function and that this
interaction (presumably occurring between the primed CD8 T cell and the
DC) occurs subsequent to 4-1BB ligation. IFN--mediated signals are
also required for the generation of functional effector cells and this,
too, appears to be subsequent to 4-1BB ligation.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: DC, dendritic cells; CD40L, CD40 ligand; Flt3L, Fms-like tyrosine kinase3 ligand; MSA, mouse serum albumin.
Received for publication January 24, 2002. Accepted for publication June 17, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in immune-evasion of cancer. Microsc. Res. Tech. 52:387.[Medline]
-interferon and -interferon on a murine renal cancer (Renca) in vitro and in vivo. Cancer Res. 50:5414. (IFN-) in tumor immunity: T cells with the capacity to reject tumor cells are generated but fail to migrate to tumor sites in IFN--deficient mice. Cancer Res. 61:3399.This article has been cited by other articles:
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
) or on days 13 and 16 (n = 10; 
).
B, C57BL/10 mice were challenged with 5 x
105 B10.2 tumor cells on day 0 and treated with rat IgG
(100 µg i.p./injection) on days 14, 17, 24, and 27
(n = 10; •), 4-1BB (M6) (150 µg i.p./injection)
on days 14 and 17 (n = 10; 
),
NK1.1-depleted (
)
Abs that have rejected prior tumors were then rechallenged s.c. with 5
x 105 B10.2 tumor cells. The tumor size represents the
average of only tumor-bearing mice, and tumor incidence is calculated
as the number of tumor-bearing over the total number of mice challenged
(x100).
) or with 4-1BB
(M6) (n = 12; 