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Immunology |
Departments of Surgery [K. S., J. J. M.] and Internal Medicine [J. J. M.], and the Tumor Immunology and Immunotherapy Program of the Comprehensive Cancer Center [J. J. M.], University of Michigan Medical Center, Ann Arbor, Michigan 48103-0666; Extramural Research, Immunex Corporation, Seattle, Washington 98101 [E. K. T.]; and Vaccines and Gene Therapy Research, Chiron Technologies, 4560 Horton Street, Emeryville, California 94608-2916 [M. G.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. D5 melanoma exposed to similar levels of IFN- results in substantial expression of MHC class I molecules. DCs pulsed with KLH and mouse tyrosinase-related protein-2 peptide results in enhanced reduction of B16 melanoma metastases; the effect is most pronounced in a setting where tyrosinase-related protein-2 peptide-pulsed DCs alone are completely ineffective. Collectively, these findings demonstrate that KLH addition to tumor antigen-pulsed DC immunizations can augment IFN- production and enhance in vivo antitumor activity. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Attention is being focused on identifying agents to enhance further T-cell reactivity to tumors elicited by DC-based vaccines, particularly with respect to those that can stimulate a potent T helper-cell response. KLH is one such molecule because it can serve as a helper antigen and induce a potent specific-memory T-cell response (9
, 10)
. For example, lymph node T cells from mice primed with DCs pulsed with KLH can secrete IL-2, IFN-, and IL-4 upon antigen rechallenge in vitro (11)
. KLH can serve as a strongly immunogenic carrier protein as well. In murine models of idiotype vaccinations, formulation of syngeneic idiotype with KLH can induce not only an anti-idiotypic antibody response, but also a T cell-proliferative response to idiotype after priming (12)
. These findings were originally explained by a "helper effect," whereby a helper determinant introduced onto an antigen presenting cell, ostensibly a DC, can promote an immunological reaction against that helper determinant. As a consequence, immunological reactivity to the accompanying tumor-specific antigen(s) increases as well (13)
. A possible mechanism(s) by which idiotype-KLH vaccines induces not only humoral responses, but also cell-mediated responses to tumor antigen(s) invokes T cells that recognize idiotype determinants that have been processed and presented as antigen epitopes by DCs, rather than as soluble idiotype (12)
.
KLH has an added advantage of being a neo-antigen and can therefore serve as an immunological tracer molecule in vaccine studies. In this respect, KLH has been shown to serve as a strong "surrogate" antigen and an immunogenic "marker" for immunization studies using DC-based vaccines (14 , 15) . In addition, KLH, when conjugated with idiotype antibody, can induce strong humoral responses in vivo, which has resulted in an objective outcome in patients with B-cell lymphoma (15) .
On the basis of these findings, we have evaluated the capacity of KLH to enhance DC-based tumor vaccines in the setting of the poorly immunogenic B16 melanoma and its subline, D5. We demonstrate that simultaneous pulsing of DCs with KLH and tumor lysates results in pronounced enhancement of vaccine-mediated immune priming and therapeutic efficacy in vivo. The addition of KLH enhances the production of IFN- by tumor-reactive T cells. Vaccine efficacy of tumor lysate/KLH-pulsed DC is augmented further by the systemic administration of IL-2.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Culture Medium.
CM consisted of RPMI 1640 supplemented with 10% heat-inactivated FCS, 0.1 mM nonessential amino acids, 1 mM sodium pyruvate, 2 mM fresh L-glutamine, 100 µg/ml streptomycin, 100 units/ml penicillin, 50 µg/ml gentamicin, 0.5 µg/ml fungizone (all from Life Technologies, Inc., Rockville, MD), and 5 x 10-5 M 2-mercaptoethanol (Sigma Chemical Co., St. Louis, MO.).
Recombinant Cytokines.
Recombinant murine GM-CSF with a specific activity of >5 x 106 units/mg (Immunex, Seattle, WA) and recombinant murine IL-4 with a specific activity 2.8 x 108 units/mg (Schering-Plough Research Institute, Kenilworth, NJ) were used to generate DCs (see below). Recombinant human IL-2 (Chiron Corp., Emeryville, CA) with a specific activity of 18 x 106 IU/mg protein was administered i.p. to mice. Murine recombinant IFN- was obtained from PharMingen, San Diego, CA (specific activity: 0.3–1 x 108 units/mg).
Tumors.
The B16-BL6 melanoma is of spontaneous origin. A poorly immunogenic, highly metastatic (accompanied by high CD44+ cell surface expression) subclone of the B16-BL6 tumor, denoted D5, has been characterized previously (16)
. The D5 melanoma expresses few to no detectable surface MHC class I molecules and no detectable surface MHC class II molecules. EL-4 is an MHC class II negative, but an MHC class I positive T-cell thymoma syngeneic to C57BL/6 mice.
Peptide.
mTRP-2 is a melanosomal membrane glycoprotein expressed on normal melanocytes and B16 melanoma. The H-2Kb-restricted mTRP-2181–188 peptide (VYDFFVWL) was synthesized by Research Genetics (Huntsville, AL).
Generation of Bone Marrow-derived DCs.
Erythrocyte-depleted mouse bone marrow cells were cultured in CM supplemented with 10 ng/ml GM-CSF and 10 ng/ml IL-4 at 1 x 106 cells/ml, as described previously (6)
. On day 6, DCs were harvested by gentle pipetting. Harvested cells were then layered onto 14.5% (w/v) metrizamide gradients, centrifuged, and the low-density interface was collected (6)
. DCs were washed twice, enumerated (purity, >80%), and used for in vitro and in vivo functional studies.
Antigen Pulsing of DCs.
On day 6, DCs were incubated with freeze-thawed (three cycles; centrifuged at 3500 rpm for 5 min; supernatant collected) D5 melanoma lysate at a ratio of three tumor cell equivalents to one DC (i.e., 3:1) in CM, as described (4
, 5)
. In separate experiments, DCs were pulsed with mTRP-2 peptide at 10 µg/ml for 18 h. After 18-h incubation, DC were harvested, washed twice in HBSS (Life Technologies, Inc.), and resuspended in HBSS for additional studies. In some experiments, DCs were coincubated with tumor lysate or with mTRP-2 peptide in the presence of 50 µg/ml KLH (subunits, Mr 350,000/400,000; endotoxin-free; Calbiochem-Novabiochem Corp., San Diego, CA).
IFN- Treatment of D5 Melanoma Cells.
D5 melanoma cells were cultured in CM containing 1,000 pg/ml mouse recombinant IFN-. At 12 h, the tumor cells were harvested, washed, and analyzed for the expression of cell surface markers by flow cytometry (fluorescence-activated cell sorting) after staining with FITC-conjugated anti-I-Ab and anti-H-2Kb mAb. Comparisons were made with appropriate isotype-matched control mAb (all from PharMingen).
Primary Immunization.
Normal B6 mice were immunized three times at 7-day intervals with KLH plus D5 TP-DCs (KLH/TP-DC). IL-2 was given i.p. twice daily at 60,000 IU in 0.5 ml HBSS for 5 days consecutively after each immunization. Control groups of mice received either no treatment (HBSS), or D5 tumor TP-DCs with or without KLH pulsing and/or with or without IL-2 administration (as detailed in Fig. 1
; Tables 1
and 2
). Mice were rechallenged with 5 x 104 viable D5 melanoma cells and then followed for survival, which was recorded as the percentage of surviving animals over time (in days) after tumor injection. Data are recorded from five or more mice/group. In separate experiments, B6 mice were immunized with mTRP-2-DCs twice at 7-day intervals and then rechallenged with 1 x 105 B16 melanoma cells. Survival was followed as described above.
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Antibody Depletion of T Cell Subsets.
In a 3-day pulmonary metastases model, on days -4 and -1 before the first immunization, groups of mice received 200 µl of ascites antibody i.v. (GK1.5, 2.43, or rat IgG) to deplete CD4+ or CD8+ T cells. Antibody treatment continued on days 2, 6, and 10 to ensure chronic depletion of the desired cell type, as described (6)
. The efficacy of depletion was analyzed by fluorescence-activated cell sorting and determined to be 99–100% effective (data not shown; Ref. 6
). On day 15 after tumor injection, splenocytes were prepared for analysis of IFN- production by standard ELISA (see below).
IFN- Assays.
Erythrocyte-depleted splenocytes (2 x 106 cells/ml) were cultured for 48 h in vitro with 2 x 105 UVB-irradiated D5, or EL-4 tumor cells in 24-well culture plates. After 48 h, culture supernatants were collected for measurement of murine IFN- release by standard ELISA (PharMingen).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, mice receiving TP-DCs alone showed 20% protection from tumor challenge, and these mice survived over 100 days (MST = 58 ± 7; P < 0.001; compared with mice receiving HBSS). Immunization with KLH/TP-DCs resulted in additional protection from tumor challenge; 40% of these mice survived over time (MST = 70 ± 9) and were rendered disease-free. Combination of low-dose IL-2 and TP-DCs also resulted in enhanced protective immunity compared with TP-DCs alone, as reported previously in our other tumor models (20)
. Forty percent of these mice experienced tumor-free survival as well (MST = 64 ± 8). In contrast, the combination of KLH/TP-DCs and IL-2 resulted in a slower tumor growth rate, and 80% of these mice survived long-term and were rendered tumor-free (MST = 90 ± 6; P = 0.006). These cured mice were rechallenged 150 days after tumor inoculation with 3 x 105 D5 melanoma cells (i.e., a 3-fold higher challenge dose); all showed complete protection. An additional cohort of the cured mice were challenged with EL-4 cells and showed no protection to this unrelated tumor (data not shown). These findings indicate that KLH can enhance the efficacy of TP-DC plus IL-2 to protect mice from lethal challenge with the poorly immunogenic D5 melanoma. In no immunized animal was autoimmune depigmentation observed.
KLH Can Enhance the Therapeutic Efficacy of DC-based Immunization against Established Tumor.
To determine the therapeutic potential of immunization with KLH/TP-DCs, we attempted to induce tumor rejection in mice with established D5 melanoma. In a 3-day treatment model, B6 mice harboring pulmonary micrometastases were treated with TP-DCs with or without KLH. As shown in Table 1
, mice receiving TP-DCs showed partial reduction (
25%) in the number of pulmonary metastases (mean = 166 ± 11; P < 0.0001; compared with mice receiving HBSS). Treatment with the combination of TP-DCs and IL-2 resulted in an additional reduction (55%) in the number of lung nodules (mean = 100 ± 11; P < 0.0001; compared with mice receiving TP-DCs). All mice treated with KLH/TP-DCs had <80 nodules (mean = 56 ± 5; P < 0.01; compared with mice treated with TP-DCs and IL-2). Furthermore, combined treatment with KLH/TP-DCs and IL-2 resulted in a significant reduction (90%) in the number of pulmonary metastases (mean =16 ± 7; P < 0.01; compared with mice receiving KLH/TP-DCs). Of importance, 9 of 15 mice experienced complete tumor regression. In no animal was autoimmune depigmentation elicited during and after treatment. Depletion of either CD4+ or CD8+ T cells by antibody treatment, as described in "Materials and Methods," abrogated the efficacy of KLH/TP-DCs to regress tumor nodules (Table 2)
, indicating that the host-derived mechanism of tumor regression mediated by DC immunizations involved both T-cell subsets. Collectively, these findings demonstrated that KLH enhanced the therapeutic efficacy of DC immunizations as well as protective immunity against a poorly immunogenic tumor, which could be enhanced further by the systemic administration of IL-2.
KLH Can Augment Tumor-specific IFN- Production.
We and others have shown previously that tumor-specific IFN- production by host-derived T cells has correlated with antitumor responses in vivo (21
, 22)
. On the basis of these findings, we hypothesized that enhancement of the efficacy of DC immunization by KLH may correlate with IFN- production by primed immune cells. To address this possibility, we next evaluated whether or not KLH/TP-DCs could elicit tumor-specific IFN- production in vivo. As shown in Fig. 2
, splenocytes from mice treated with TP-DCs and IL-2 produced greater amounts of IFN- (13,700 ± 1,700 pg/ml; P < 0.05) in response to relevant tumor than those receiving TP-DCs (4,800 ± 500 pg/ml). In addition, splenocytes from mice treated with KLH/TP-DCs resulted in an additionally significant IFN- production (20,200 ± 2,800 pg/ml; P < 0.01) compared with mice receiving TP-DCs, which was augmented >2-fold by the inclusion of IL-2 (51,200 ± 11,000 pg/ml; P < 0.05). Splenocytes from the control groups of mice produced undetectable levels of IFN- (<97.5 pg/ml). Thus, IFN- production correlated with in vivo antitumor activity (Table 1)
. In contrast, splenocytes from treated mice showed little, if any, detectable levels of IL-4 production (data not shown), indicating that DC immunization with or without KLH pulsing induced a Th1 immune response in vivo. As shown in Table 3
, in vivo depletion of host-derived CD4+ T cells completely abrogated IFN- production by the harvested splenocytes (1,100 ± 100 pg/ml), demonstrating that IFN- production in vivo was indeed CD4-dependent. We also evaluated IFN- production by splenocytes from mice treated with KLH/TP-DCs in response to KLH protein stimulation. Splenocytes from the immunized mice were stimulated with either irradiated D5 melanoma cells or KLH protein in vitro. At 48 h, supernatants were collected. The cells produced IFN- specifically in response to stimulation by KLH protein (9,729 ± 588 pg/ml; P < 0.001) as well as to the D5 melanoma, indicating that TP-DCs with KLH pulsing may "educate" naïve T cells capable of responding to KLH as well as to tumor antigen(s), respectively.
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-treated D5 Melanoma Cells. production correlated with in vivo antitumor activity, we determined whether or not IFN- produced by effector cells in vivo may influence the characteristics of D5 melanoma cells. As shown in Fig. 3
, D5 melanoma cells expressed only very low levels of surface MHC class I molecules and no detectable surface MHC class II molecules. In contrast, IFN- exposure of D5 melanoma cells resulted in a substantial up-regulation of MHC class I (Fig. 3)
. Expression of surface MHC class II and CD95/Fas was low or absent on D5 melanoma cells with or without IFN- (data not shown).
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, mice receiving mTRP-2-DCs showed complete protection from tumor challenge (P < 0.0001). These tumor-free mice were rechallenged 90 days after tumor inoculation with 3 x 105 B16 melanoma cells (3-fold higher number than previous challenge), or with EL-4 tumor cells. All mice showed complete protection from rechallenge with the former, but not the latter, tumor cells (data not shown). These initial findings indicated that immunization with mTRP-2-DCs elicited a strong protective immunity as well as a memory response to B16 melanoma.
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, treatment with mTRP-2-DCs alone resulted in no reduction in the number of established pulmonary metastasis (mean = 250). Thus, although mTRP-2-DCs could effectively prime mice to reject a lethal challenge of viable B16 melanoma cells, the vaccine by itself failed to have any impact on established tumor. The combination of mTRP-2-DCs and IL-2 demonstrated a modest, but significant, reduction in the number of pulmonary metastases (mean = 220 ± 3; P < 0.001; compared with mice receiving mTRP-2-DCs alone). In contrast, mice treated with KLH/mTRP-2-DCs experienced partial reduction (25%) in the number of pulmonary nodules (mean = 188 ± 7; P < 0.01). Of importance, IL-2 administration further enhanced the efficacy of KLH/mTRP-2-DCs to regress pulmonary nodules by 60% (mean = 102 ± 10; P < 0.01).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the current study, the systemic administration of IL-2 at relatively high doses (60,000 IU/dose) enhanced TP-DC-based immunizations to promote protective immunity toward and therapeutic rejection of the B16 melanoma and its subline, D5. Thus, unlike in our previous work with sarcoma and mammary tumor, treatment of these melanomas by TP-DCs plus IL-2 required higher doses of IL-2 to promote antitumor activity. Attempts to escalate the IL-2 dose beyond 60,000 IU to achieve greater antitumor effects when combined with TP-DC immunization were not possible because of dose-limiting toxicity. Toxicity from high-dose IL-2 administration has been reported previously in both animals and humans, which has hampered its wider use as an agent in cancer therapy (23, 24, 25) . Given this limitation, we attempted to combine IL-2 with a foreign helper protein.
We demonstrated that KLH, a strongly immunogenic carrier protein, could augment the efficacy of tumor lysate- or TRP-2 peptide-pulsed DC immunization in mediating both successful immune priming toward and therapeutic rejection of the B16 melanoma and its subline, D5. These effects could be further enhanced by the systemic administration of IL-2 and were dependent on host-derived CD4+ T cells. CD4+ T cells from mice treated with KLH/TP-DCs could secrete elevated amounts of the Th1-type cytokine, IFN-, in a specific fashion after exposure to melanoma cells. Furthermore, IFN- exposure of the melanoma cells resulted in a marked up-regulation of MHC class I molecules.
The level of expression of MHC class I molecules on tumor cells is an important determinant of their interaction with CTLs (26
, 27) . A variety of cytokines have been shown to augment MHC expression on tumor cells in vitro (28
, 29)
. Moreover, Weber et al. (27
, 30)
demonstrated that in vivo treatment of mice bearing s.c. B16 melanoma with the systemic administration of recombinant IFN- could up-regulate tumor expression of MHC class I, but not class II, molecules. This process resulted in both an enhanced sensitivity of the B16 melanoma to treatment with recombinant IL-2 and the generation of specific, therapeutic tumor-infiltrating lymphocytes. In our previous study (20)
, we demonstrated that splenocytes from mice immunized with TP-DCs could produce IFN- (>2,000 pg/ml) when stimulated in vitro with relevant TP-DCs. On the basis of these findings, we sought to determine whether IFN- could up-regulate the expression of MHC molecules on melanoma cells. Indeed, surface expression of MHC class I molecules by D5 melanoma cells was strikingly elevated by relatively low-dose (1,000 pg/ml) IFN- treatment in vitro.
With respect to the use of B16 and D5 melanoma lysates as the source of antigen(s) for pulsing of DCs, in no case of primary immunization nor treatment of established tumors did we observe any animal develop autoimmunity as manifested by depigmentation subsequent to the elicitation of potent antitumor immunity in vivo. This finding is seemingly at odds with those reported by others in which mice immunized with either TRP-1 (31 , 32) or intact B16 melanoma cells (33) developed marked depigmentation with successful tumor immunity. These contradictory observations, albeit in similar tumor models, underscore the intricacy and the additional need to study the relationship between tumor immunity and autoimmunity. The complete lack of induction of discernable depigmentation by TP-DC immunization in our experience might be explained by differences in the strategies used for immunization (e.g., DCs versus recombinant vaccinia virus, DNA, or GM-CSF and CTLA-4 blockade) or by the lack of processing and presentation by TP-DCs of the antigen(s) responsible for autoimmune reactivity and the induction of autoantibodies or autoreactive CD8+ T cells. Unlike B lymphocytes, DCs have been reported to focus the immune response against select antigenic determinants (34) . Alternatively, the density of the particular antigen(s) presented by TP-DCs could have affected the outcome of the induced immune response in vivo (35) .
Idiotype-KLH vaccines have been shown to induce not only humoral responses but also cell-mediated responses to tumor antigen(s). These responses were presumably dependent on T cells that recognized idiotype determinants processed and presented as antigen epitopes by DCs, rather than as soluble idiotype (10)
. On the basis of these studies, we hypothesized that the mechanism(s) by which KLH could augment the therapeutic efficacy of TP-DC-based immunization was dependent on CD4+ T cells. Indeed, depletion of CD4+ T cells in mice harboring 3-day pulmonary metastases from the D5 melanoma completely abrogated the efficacy of KLH to augment the effect of DC-based immunization on tumor growth (Table 2)
. Moreover, production of IFN- was eliminated by the depletion of CD4+ T cells (Table 3)
. These findings corroborate those of Schnell et al. (36)
, which demonstrated the necessity of CD4+ T-cell help to elicit antitumor activity in the setting of DC immunization.
In our previous studies, we showed that the immune priming and therapeutic activity mediated by TP-DCs were dependent predominantly on host-derived CD8+ and, to a lesser extent, on CD4+ T cells in both a murine fibrosarcoma and a breast tumor model (6)
. In contrast, in vivo growth of B16 melanomas could be eradicated by various effector cells such as natural cell-mediated cytotoxicity (37)
, activated macrophages (38
, 39)
, CD4+ T cells (40)
, or CD8+ CTLs (39
, 41, 42, 43)
. In our current study, depletion studies demonstrated that the effect of TP-pulsed DCs on pulmonary metastases was critically dependent on both CD4+ and CD8+ T cells. These findings showed that a mixture of tumor lysates and strongly immunogenic carrier protein, KLH, could augment the function of CD4+ T cells to produce a Th1 cytokine, namely IFN-, and generate CD8+ T cell activity. These results differ from those recently reported by Timmerman and Levy (44)
. In the latter study, Id-KLH-pulsed DC immunization resulted in a potent elicitation of anti-Id antibodies and tumor regression but surprisingly was not dependent on effector T cells.
Some recent human clinical trials by us (45)
and by others (14
, 15)
to evaluate DC-based cancer vaccines have used KLH in addition to a source of tumor antigen(s) for immunization. In the current study, DCs pulsed simultaneously with both KLH and mouse TRP-2 peptide resulted in an enhanced reduction of established B16 melanoma metastases. This effect was most pronounced in a setting where TRP-2-pulsed DC immunizations alone were completely ineffective in impacting on established B16 melanoma metastases (Table 4)
. These results also suggest that DC-based tumor vaccine strategies may benefit by the addition of KLH, particularly in the setting of CTL-defined tumor peptides.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by grants from the National Cancer Institute, NIH (2 R01CA71669, 1 R01 CA87019, 5 P01 CA59327, and M01-RR00042), from the Department of Defense, United States Army (DAMD17-96-1-6103 and DAAG55-97-1-0239), and by a gift from C. J. and E. C. Aschauer, and Abbott Laboratories. 
2 To whom requests for reprints should be addressed, at Department of Surgery, University of Michigan Medical Center, 1520c MSRB-1, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0666; Phone: (734) 647-2779; Fax: (734) 763-4135; E-mail: jimmule{at}umich.edu
3 The abbreviations used are: DC, dendritic cell; KLH, keyhole limpet hemocyanin; IL, interleukin; CM, complete medium; HBSS, Hanks’ balanced salt solution; B6, C57BL/6J; TNF-
, tumor necrosis factor-; GM-CSF, granulocyte/monocyte colony-stimulating factor; TP-DC, tumor lysate-pulsed DC; TRP, tyrosinase-related protein; mTRP-2, murine TRP-2; mAb, monoclonal antibody; mTRP-2-DC, mTRP-2 peptide-pulsed DC; MST, mean survival time;
Received 9/27/00. Accepted 1/16/01.
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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