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,
*
University of California, Los Angeles, Medical School-Wadsworth Pulmonary Laboratory, Veterans Administration West Los Angeles Healthcare Center,
Jonsson Comprehensive Cancer Center, and
Division of Pulmonary and Critical Care Medicine, University of California, Los Angeles, Medical School, Los Angeles, CA 90073
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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and IFN--inducible protein 10
but a concomitant decrease in immunosuppressive cytokines at the tumor
site. In response to irradiated autologous tumor, splenic and lymph
node-derived cells from SLC-treated tumor-bearing mice secreted
significantly more IFN-, GM-CSF, and IL-12 and reduced levels of
IL-10 than did diluent-treated tumor-bearing mice. After stimulation
with irradiated autologous tumor, lymph node-derived lymphocytes from
SLC-treated tumor-bearing mice demonstrated enhanced cytolytic
capacity, suggesting the generation of systemic immune responses. These
findings provide a strong rationale for further evaluation of SLC in
tumor immunity and its use in cancer
immunotherapy. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Chemokines are a group of homologous yet functionally divergent proteins that directly mediate leukocyte migration and activation and play a role in regulating angiogenesis (6). Chemokines also function in maintaining immune homeostasis and secondary lymphoid organ architecture (7). Secondary lymphoid organ chemokine (SLC),3 a CC chemokine expressed by high endothelial venules and in T cell zones of spleen and lymph nodes, strongly attracts naive T cells and mature dendritic cells (DC) (8, 9, 10, 11, 12, 13, 14, 15). DC are uniquely potent APC involved in the initiation of immune responses (16). Serving as immune system sentinels, DC are responsible for Ag acquisition in the periphery and subsequent transport to T cell areas in lymphoid organs where they prime specific immune responses. SLC recruits both naive lymphocytes and Ag-stimulated DC into T cell zones of secondary lymphoid organs, colocalizing these early immune response constituents and culminating in cognate T cell activation (8). The importance of SLC in T cell homing was recently demonstrated by Gunn et al. (17). Mutant plt/plt mice that have a defective gene encoding SLC had impaired T cell homing to secondary lymphoid organs. SLC mediates its effects through two specific G protein-coupled seven-transmembrane domain chemokine receptors, CCR7 and CXCR3 (18, 19). Whereas CCR7 is expressed on naive T cells and mature DC, CXCR3 is expressed preferentially on Th1 cytokine-producing lymphocytes with memory phenotype (18, 19). Thus, we speculated that the capacity of SLC to facilitate the colocalization of both DC and T cells could reverse tumor-mediated immune suppression and orchestrate effective cell-mediated immune responses. A potentially effective pathway to restore Ag presentation is the establishment of a chemotactic gradient that favors localization of activated DC within the tumor site. We hypothesized that intratumoral injection of SLC would lead to chemoattraction of mature DC and naive T cells to the tumor site and produce immune-dependent tumor reduction. In this study, utilizing two well-established lung cancer models, we show that intratumoral injection of SLC evidenced significant reductions in tumor volumes with complete tumor eradication in 40% of the mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Two weakly immunogenic lung cancers, line 1 alveolar carcinoma (L1C2, H-2d) and Lewis lung carcinoma (3LL, H-2b), were utilized for assessment of antitumor responses in vivo. The cells were routinely cultured as monolayers in 25-cm3 tissue culture flasks containing RPMI 1640 (Irvine Scientific, Santa Ana, CA) supplemented with 10% FBS (Gemini Bioproducts, Calabasas, CA), penicillin (100 U/ml), streptomycin (0.1 mg/ml), 2 mM glutamine (JRH Biosciences, Lenexa, KS) and maintained at 37°C in a humidified atmosphere containing 5% CO2 in air. The cell lines were Mycoplasma free, and cells were utilized up to the tenth passage before thawing frozen stock cells from liquid N2. For tumorigenesis experiments, 105 3LL or L1C2 tumor cells were inoculated by s.c. injection in the right suprascapular area of C57BL/6 or BALB/c mice, and tumor volume was monitored three times per week. Five-day-old established tumors were treated with intratumoral injection of 0.5 µg of murine recombinant SLC or PBS diluent (Pepro Tech, Rocky Hill, NJ) administered three times per week for 2 weeks. The endotoxin level reported by the manufacturer was <0.1 ng/µg (1 EU/µg) of SLC. The amount of SLC (0.5 µg) used for injection was determined by the in vitro biological activity data provided by the manufacturer. Maximal chemotactic activity of SLC for total murine T cells was 100 ng/ml. For in vivo evaluation of SLC-mediated antitumor properties, we utilized 5-fold more than this amount for each intratumoral injection. Tumorigenesis experiments were also performed in which equivalent amounts of murine serum albumin were utilized (Sigma, St. Louis, MO) as an irrelevant protein for control injections. Experiments were also performed in which the SLC was administered at the time of tumor inoculation. To determine the importance of the immune system in mediating antitumor responses after SLC administration, tumorigenesis experiments were conducted in SCID beige CB17 mice. SLC was administered s.c. at the time of tumor inoculation and then three times per week. CD4 and CD8 knockout mice were utilized to determine the contribution of CD4 and CD8 cells in tumor eradication. Two bisecting diameters of each tumor were measured with calipers. The volume was calculated using the formula (0.4) (ab2), with a as the larger diameter and b as the smaller diameter.
Cytokine determination from tumor nodules, lymph nodes, and spleens
The cytokine profiles in tumors, lymph nodes, and spleens were
determined in both SLC and diluent-treated mice as previously described
(4). Nonnecrotic tumors were harvested, cut into small
pieces, and passed through a sieve (Bellco Glass, Vineland, NJ).
Tumor-draining lymph nodes and spleens were harvested from SLC-treated
tumor-bearing, control tumor-bearing, and normal control mice. Lymph
nodes and spleens were teased apart, RBC depleted with double-distilled
H2O, and brought to tonicity with 1x PBS. Tumor
nodules were evaluated for the production of IL-10, IL-12, GM-CSF,
IFN-, TGF-ß, vascular endothelial growth factor (VEGF), monokine
induced by IFN- (MIG), and IP-10 by ELISA and
PGE2 by enzyme immunoassay (EIA) in the
supernatants after an overnight culture. Tumor-derived cytokine and
PGE2 concentrations were corrected for total
protein by Bradford assay (Sigma, St. Louis, MO). For cytokine
determinations after secondary stimulation with irradiated tumor cells
(5 x 10 6 cells/ml), splenic or lymph
node-derived lymphocytes were cocultured with irradiated 3LL
(105 cells/ml) at a ratio of 50:1 in a total
volume of 5 ml. After an overnight culture, supernatants were harvested
and GM-CSF, IFN-, IL-12, and IL-10 determined by ELISA.
Cytokine ELISA
Cytokine protein concentrations from tumor nodules, lymph nodes
and spleens were determined by ELISA as previously described
(20). Briefly, 96-well Costar (Cambridge, MA) plates were
coated overnight with 4 µg/ml of the appropriate anti-mouse mAb
to the cytokine being measured. The wells of the plate were blocked
with 10% fetal bovine serum (Gemini Bioproducts) in PBS for 30 min.
The plate was then incubated with the Ag for 1 h, and excess Ag
was washed off with PBS-Tween. The plate was incubated with 2 µg/ml
biotinylated mAb to the appropriate cytokine (PharMingen, San Diego,
CA) for 30 min, and excess Ab was washed off with PBS-Tween. The plates
were incubated with avidin peroxidase, and after incubation in OPD
substrate to the desired extinction, the subsequent change in color was
read at 490 nm with a Microplate Reader (Molecular Dynamics, Sunnyvale,
CA). The recombinant cytokines used as standards in the assay were
obtained from PharMingen. IL-12 (Biosource) and VEGF (Oncogene Research
Products, Cambridge, MA) were determined by kits according to the
manufacturer’s instructions. MIG and IP-10 were quantified by a
modification of a double ligand method as previously described
(21). The MIG and IP-10 Abs and protein were from R&D
(Minneapolis, MN). The sensitivities of the IL-10, GM-CSF, IFN-,
TGF-ß, MIG, and IP-10 ELISA were 15 pg/ml. For IL-12 and VEGF, the
sensitivities were 5 pg/ml.
PGE2 EIA
PGE2 concentrations were determined using a kit from Cayman Chemical (Ann Arbor, MI) according to the manufacturer’s instructions as previously described (3). The EIA plates were read by a Molecular Dynamics Microplate Reader.
Cytolytic experiments
Cytolytic activity was assessed as previously described (4). To quantify tumor cytolysis after a secondary stimulation with irradiated tumor cells, lymph node-derived lymphocytes (5 x 106 cells/ml) from SLC-treated and diluent tumor-bearing mice were cultured with irradiated 3LL (105 cells/ml) tumors at a ratio of 50:1 in a total volume of 5 ml. After a 5-day culture, the lytic capacity of lymph node-derived lymphocytes were determined against chromium-labeled (51Cr, Amersham Arlington, Heights, IL; sp. act. 250–500 mCi/mg) 3LL targets at varying E:T ratios for 4 h in 96-well plates. Spontaneous release and maximum release with 5% Triton X also were assessed. After the 4-h incubation, supernatants were removed and activity was determined with a gamma counter (Beckman, Fullerton, CA). The percent specific lysis was calculated by the formula: % lysis = 100 x (experimental cpm - spontaneous release)/(maximum release - spontaneous release).
Flow cytometry
For flow cytometric experiments, two or three fluorochromes (PE, FITC, and Tri-color) (PharMingen) were used to gate on the CD3 T lymphocyte population of tumor nodule single-cell suspensions. DCs were defined as the CD11c and DEC 205 bright populations within tumor nodules and lymph nodes. Cells were identified as lymphocytes or DC by gating based on forward and side scatter profiles. Flow cytometric analyses were performed on a FACScan flow cytometer (Becton Dickinson, San Jose, CA) in the University of California, Los Angeles, Jonsson Cancer Center Flow Cytometry Core Facility. Between 5,000 and 15,000 gated events were collected and analyzed using Cell Quest software (Becton Dickinson).
Intracellular cytokine analysis
T lymphocytes from single-cell suspensions of tumor nodules and
lymph nodes of SLC-treated and diluent-treated 3LL tumor-bearing mice
were depleted of RBC with distilled, deionized
H2O and were evaluated for the presence of
intracytoplasmic GM-CSF and IFN-. Cell suspensions were treated with
the protein transport inhibitor kit GolgiPlug (PharMingen) according to
the manufacturer’s instructions. Cells were harvested and washed twice
in 2% FBS-PBS. Cells (5 x 105) cells were
resuspended in 200 µl of 2% FBS-PBS with 0.5 µg FITC-conjugated
mAb specific for cell surface Ags CD3, CD4, and CD8 for 30 min at
4°C. After two washes in 2% FBS-PBS, cells were fixed,
permeabilized, and washed using the Cytofix/Cytoperm Kit (PharMingen)
following the manufacturer’s protocol. The cell pellet was resuspended
in 100 µl Perm/Wash solution and stained with 0.25 µg PE-conjugated
anti-GM-CSF and anti-IFN- mAb for intracellular staining.
Cells were incubated at room temperature in the dark for 30 min, washed
twice, resuspended in 300 µl PBS, 2% paraformaldehyde solution, and
analyzed by flow cytometry.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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, A
and D). To determine whether the decrease in tumor volumes
resulted from a direct effect of SLC on L1C2 and 3LL, the in vitro
proliferation of the tumor cells was assessed in the presence of SLC.
SLC (200 ng/ml) was added to 105 L1C2 and 3LL
cells plated in 12-well Costar plates, and cell numbers were monitored
daily for 3 days. SLC did not alter the in vitro proliferation rates of
these tumor cells (data not shown).
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E). Similarly, in CD4 and CD8 knockout mice, SLC
failed to reduce tumor volumes, indicating that SLC-mediated antitumor
responses were both CD4 and CD8 dependent (Fig. 1, B and
C).
On the basis of previous reports indicating that tumor progression can
be modified by host cytokine profiles (22, 23), we
evaluated the cytokine production from tumor nodules after intratumoral
SLC administration. The following cytokines were measured: VEGF, IL-10,
PGE2, TGF-ß, IFN-, GM-CSF, IL-12, MIG, and
IP-10 (Table I). The production of these
cytokines were evaluated for the following reasons. The tumor site has
been documented to be an abundant source of PGE-2, VEGF, IL-10, and
TGF-ß, and the presence of these molecules at the tumor site have
been shown to suppress immune responses (3, 24, 25). VEGF,
PGE2, and TGF-ß have also previously been
documented to promote angiogenesis (26, 27, 28). Abs to VEGF,
TGF-ß, PGE-2 and IL-10 have the capacity to suppress tumor growth in
in vivo model systems. VEGF has also been shown to interfere with DC
maturation (25). Both IL-10 and TGFß are immune
inhibitory cytokines that may potently suppress Ag presentation and
antagonize CTL generation and macrophage activities, thus enabling the
tumor to escape immune detection (4, 24). Compared with
tumor nodules from diluent-treated tumor-bearing controls, mice treated
intratumorally with SLC had significant reductions of
PGE2 (3.5-fold), VEGF (4-fold), IL-10 (2-fold)
and TGF-ß (2.3-fold) (Table I). An overall decrease in IL-10 and
TGFß at the tumor site after SLC administration may have promoted Ag
presentation and CTL generation. The decrease in VEGF and TGF-ß at
the tumor site after SLC administration may have contributed to an
inhibition of angiogenesis. In contrast, there was a significant
increase in IFN- (5-fold), GM-CSF (10-fold), IL-12 (2-fold), MIG
(6.6-fold), and IP-10 (2-fold) after SLC administration (Table I).
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is a type
1 cytokine that promotes cell-mediated immunity. Increases in IL-12
(2-fold) could explain the relative increase in IFN- (5-fold) at the
tumor site of SLC-treated mice (Table I). The tumor cells used for this
study do not make detectable levels of IL-12 (data not shown). We
therefore anticipate that macrophages and DC are the predominant
sources of IL-12 at the tumor site.
MIG and IP-10 are potent angiostatic factors that are induced by
IFN- and may be responsible, in part, for IL-12-mediated tumor
reduction (29, 30, 31). Hence, an increase in IFN- at the
tumor site of SLC-treated mice could explain the relative increase in
MIG (6.6-fold) and IP-10 (2-fold) (Table I). Both MIG and IP-10 are
chemotactic for stimulated CXCR3-expressing T lymphocytes, and this
could also increase IFN- at the tumor site (32). An
increase in GM-CSF (10-fold) in the tumor nodules of SLC treated mice
could enhance DC maturation and Ag presentation (16).
Based on the current results, it is not yet clear that the decrease in
immunosuppressive cytokines and concomitant increase in type 1
cytokines is a direct effect of SLC on the cells resident within the
tumor nodules. Alternatively, these changes could be a result of
SLC-recruited T cells and DC. To begin to address this question, we
evaluated the production of type 1 and immunosuppressive cytokines from
tumor- and lymph node-derived cells in response to SLC in vitro. Tumor
cells (1 x 106) or lymph node-derived cells
(5 x 10 6) were cocultured with SLC (200
ng/ml) for 24 h for cytokine determinations. SLC did not affect
tumor cell production of VEGF, TGF-ß, IL-10, or
PGE2 (data not shown). Compared with the control
untreated lymph node cells SLC significantly increased lymph
node-derived IL-12 (288 ± 15 pg/ml vs 400 ± 7 pg/ml) while
decreasing IL-10 (110 ± 5 pg/ml vs 67 ± 1 pg/ml),
PGE2 (210 ± 4 pg/ml vs 70 ± 2 pg/ml),
and TGF-ß (258 ± 9 pg/ml vs 158 ± 7 pg/ml) production in
an overnight in vitro culture. SLC did not alter lymph node-derived
lymphocyte production of IFN- and GM-CSF in vitro (data not shown).
Because SLC is documented to have antiangiogenic effects (33, 34), the tumor reductions observed in these models may be due to
T cell-dependent immunity as well as a participation by T cells in
inhibiting angiogenesis (30). Further studies will be
necessary to delineate the cell types and proteins critical for the
decrease in immunosuppressive cytokines and the increase in type 1
cytokines after SLC administration.
To determine whether the increase in GM-CSF and IFN- in the tumor
nodules in response to SLC could be explained by an increase in the
frequency of CD4 and CD8 T cell subsets secreting these cytokines, flow
cytometric analyses were performed. CD3 T cells that stained positively
for cell surface markers CD4 or CD8 were evaluated in single-cell
suspensions from tumor nodules. In the tumor nodules of SLC-treated
mice, within the gated T lymphocyte population, there was a significant
increase in the frequency of CD4 and CD8 T lymphocytes in comparison to
diluent-treated mice (25 and 33% vs 15 and11%, respectively;
p < 0.01). The GM-CSF and IFN- profile of CD4 and
CD8 T cells at the tumor sites and lymph nodes were determined by
intracytoplasmic staining. SLC administration resulted in an increased
frequency of CD4 and CD8 T lymphocytes from tumor nodules and lymph
nodes secreting GM-CSF and IFN- (Table II).
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). These findings
indicate that intratumoral SLC administration effectively recruited DC
to the tumor site
We next asked whether intratumoral SLC administration could induce
significant systemic immune responses. To address this question, lymph
node and splenocytes from SLC and diluent-treated tumor-bearing mice
were cocultured with irradiated tumor cells for 24 h, and GM-CSF,
IFN-, IL-10, and IL-12 levels were determined by ELISA. After
secondary stimulation with irradiated tumor cells, splenocytes and
lymph node-derived cells from SLC-treated tumor-bearing mice secreted
significantly increased levels of IFN- (13- to 28-fold), GM-CSF
(3-fold spleen only) and IL-12 (1.3- to 4-fold). In contrast, IL-10
secretion was reduced (6- to 9-fold) in SLC-treated mice (Table III). Moreover, intratumoral SLC
administration led to enhanced lymph node-derived lymphocyte cytolytic
activity against the parental tumor cells (Fig. 2). We speculate that the phenotype of
the effector cell population in the cytolytic experiments is
CD8+ T lymphocytes because SLC did not affect
tumor growth in SCID mice. However, tumorigenesis experiments utilizing
CD4 and CD8 knockout mice demonstrate the importance of both CD4 and
CD8 T lymphocytes subsets for effective tumor reduction. Because CD4 T
lymphocytes can also act as cytolytic effectors (35, 36),
further studies will be required to delineate the role of CD4 T
lymphocytes in SLC-mediated tumor reduction.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Steven M. Dubinett, Division of Pulmonary and Critical Care Medicine, School of Medicine, 37-131 Center for Health Sciences, 10833 LeConte Avenue, Los Angeles, CA 90095-1690.
3 Abbreviations used in this paper: SLC, secondary lymphoid organ chemokine; DC, dendritic cells; 3LL, Lewis lung carcinoma; VEGF, vascular endothelial growth factor; MIG, monokine induced by IFN-; IP-10, IFN--inducible protein 10; EIA, enzyme immunoassay.
Received for publication December 6, 1999. Accepted for publication February 22, 2000.
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