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[Cancer Research 64, 2162-2166, March 15, 2004]
© 2004 American Association for Cancer Research

Immunology

A Mimic of Tumor Rejection Antigen-Associated Carbohydrates Mediates an Antitumor Cellular Response

Behjatolah Monzavi-Karbassi1, Ping Luo2, Fariba Jousheghany1, Marta Torres-Quiñones2, Gina Cunto-Amesty2, Cecile Artaud1 and Thomas Kieber-Emmons1

1 University of Arkansas for Medical Sciences, Little Rock, Arkansas, and 2 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Tumor-associated carbohydrate antigens are typically perceived as inadequate targets for generating tumor-specific cellular responses. Lectin profile reactivity and crystallographic studies demonstrate that MHC class I molecules can present to the immune system posttranslationally modified cytosolic peptides carrying O-ß-linked N-acetylglucosamine (GlcNAc). Here we report that a peptide surrogate of GlcNAc can facilitate an in vivo tumor-specific cellular response to established Meth A tumors that display native O-GlcNAc glycoproteins on the tumor cell surface. Peptide immunization of tumor-bearing mice had a moderate effect on tumor regression. Inclusion of interleukin 12 in the immunization regimen stimulated complete elimination of tumor cells in all of the mice tested, whereas interleukin 12 administration alone afforded no tumor growth inhibition. Adoptive transfer of immune T cells into tumor-bearing nude mice indicates a role for CD8+ T cells in tumor regression. This work postulates that peptide mimetics of glycosylated tumor rejection antigens might be further developed for immune therapy of cancer.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The presence of carbohydrate antigens on the surface of common human malignant tumor cells has led to studies directed toward the development of synthetic carbohydrate-based anticancer vaccines (1) . Although these vaccines elicit antibody responses, it would also be advantageous if T cells could be directed to tumor-associated carbohydrate antigens (2, 3, 4, 5, 6) . Posttranslationally modified cytosolic peptides carrying O-ß-linked N-acetylglucosamine (GlcNAc) can be presented by class I MHC molecules to the immune system that activate CTLs, as resolved by wheat germ agglutinin (WGA)-binding profiles reacting with GlcNAc containing glycopeptides in the MHC Class I binding site (7 , 8) . Crystal structure analysis of T-cell receptor binding to model glycopeptides has indeed shown that T cells can recognize GlcNAc-linked glycopeptides bound by the MHC molecule (9 , 10) . T cells, therefore, have the potential to react with the GlcNAc moiety of glycopeptide antigens, suggesting that T cells can target to presented carbohydrate antigens on tumor cells.

In an effort to further define strategies to augment immune responses to tumor cells, we have been developing peptide mimics of tumor-associated carbohydrate antigens and have demonstrated that peptides synthesized as multivalent peptides can emulate or mimic the native clustering or presentation of tumor cell-displayed carbohydrate antigens (11) . We have shown that prophylactic vaccination with a peptide surrogate, having the sequence GGIYWRYDIYWRYDIYWRYD (and referred to as peptide 106), induces a tumor-specific humoral response inhibiting tumor growth of a methylcholanthrene-induced sarcoma cell line (Meth A) in vivo (11) . This peptide also activates an in vitro Meth A-specific cellular response with IFN-{gamma} production on activation of lymphocytes with peptide (12) . Characterization of the cellular response indicated that peptide-specific CD8+ T cells played an important role in mediating the tumor-specific CTL response that was inhibited by anti-Class I antibody (12) .

Here, we demonstrate the ability of this peptide to stimulate the regression of established Meth A tumor in a murine model via the activation of specific antitumor cellular responses. We demonstrate that peptide 106 is a mimic of O-GlcNAc, an antigen presented on Meth A surface-expressed glycoproteins as resolved by reactivity with WGA to which the peptide also binds. Immunohistochemistry demonstrates infiltrates of lymphocytes targeting Meth A tumor cells in peptide-immunized mice and adoptive transfer of peptide-specific T cells into tumor-bearing nude mice verifies a role for CD8+ T cells in mediating tumor regression. These studies highlight a new function for peptide mimotopes of carbohydrate-associated antigens by demonstrating that they possess in vivo antitumor activity with CD8+ T cells as the primary effector cells.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Mice and Tumor Inoculation.
BALB/c female mice, 6–8 weeks old, were purchased from The Jackson Laboratory (Bar Harbor, ME). BALB/c nude mice (BALB/cAnNTac-Foxn1nu N9, nu/nu) were purchased from Taconic Farm Inc. (Germantown, NY). To establish tumor, each mouse was inoculated s.c. into the right flank with 5 x 105 Meth A cells (Methylcholanthrene-induced sarcoma of BALB/c origin; Ref. 11 ). Tumor growth was measured using a caliper and was recorded as the mean of two orthogonal diameters [(a + b)/2].

Immunization.
As in our previous studies (11 , 12) , peptide 106, having the sequence GGIYWRYDIYWRYDIYWRYD, was synthesized as a multiple-antigen peptide (Research Genetics, Huntsville, AL). Each mouse received 100 µg of 106 multiple-antigen peptide and 20 µg of QS-21 (Antigenics Inc., Framingham, MA) i.p., both resuspended in 100 µl of PBS three times at 5-day intervals. Recombinant murine interleukin (IL)-12 (Sigma, St. Louis, MO) was administered i.p. once daily for 5 days, starting on the day of the last peptide immunization.

Flow Cytometry.
Acquisition and analysis were performed as described earlier (12) . Cells were resuspended in a buffer containing, Dulbecco’s PBS, 1% BSA, and 0.1% sodium azide and incubated with biotinylated peanut agglutinin or WGA (10 µg/ml; Vector laboratories, Burlingame, CA) for 30 min on ice. Cells were then stained with FITC-conjugated streptavidin at 1:500 dilution for another 30 min on ice.

ELISA and Inhibition Assays.
ELISA was performed as described previously (11) . Briefly, plates were coated with 106 multiple-antigen peptide. Biotinylated WGA was added, and binding was visualized with streptavidin-horseradish peroxidase (Sigma, St. Louis, MO). Absorbance was read, using a Bio-Tek ELISA reader (Bio-Tek instruments, Inc, Highland Park, Vermont). For inhibition assay, GlcNAc and N-acetylgalactosamine, attached to a polyacrylamide polymer (GlycoTech Corporation, Rockville, MA), were used as carbohydrate competitor. Biotinylated WGA (2.5 µg/ml) combined with serial concentrations of carbohydrates and incubated overnight at +4°C. Lectin/carbohydrate mix was added to the peptide-coated plates, and lectin binding was visualized by streptavidin-horseradish peroxidase as above. Mean absorbance was calculated from duplicates for each carbohydrate concentration, and percentage of inhibition was calculated as: {1 - (mean of test wells/mean of control wells)} x 100.

T-Cell Purification.
Splenocytes were harvested from spleens and prepared by lysis of erythrocytes and consequent washing several times with fresh medium (12) . Splenocytes were first passed through nylon wool and then, using MiniMACS (Miltenyi Biotec, Auburn, CA), natural killer cells were depleted using anti-natural killer cell (DX5) microbeads. Finally, T cells were positively purified by Thy1.2-coated beads. Purified T cells were tested for purity as >97% positive for anti-CD3 antibody. For cell transfer experiments, after nylon wool passage, cells were enriched in CD4+ or CD8+ population using MiniMACS and depletion of unwanted cell populations.

IFN-{gamma} Production by Purified T Cells.
Purified T cells (1 x 106/ml) were cultured in 96-well or 24-well plates with various doses of recombinant IL-12. After 48 h of stimulation, supernatant was harvested and stored at -20 until use. Concentration of IFN-{gamma} was measured using a quantitative ELISA kit (BioSource International Inc., Camarillo, CA) according to the manufacturer’s instructions.

Adoptive Transfer of Cells.
Splenocytes were collected from cured mice after tumor eradication and were used in transfer experiments. Immune splenocytes (1.5 x 107) were transferred i.p. to syngeneic nude tumor-bearing mice 7 to 10 days after inoculation of 0.5 x 106 Meth A cells into the right flank. To in vitro deplete CD4+ and CD8+ cells, splenocytes (1.5 x 107/each sample) were first passed through nylon wool column, and then, using MACS, we depleted CD4+ and CD8+ cells.

Histology.
Tumors with surrounding tissues were excised and fixed in 10% formalin. Fixed samples were embedded in paraffin, sectioned, and stained with H&E. Sections were analyzed histologically for lymphocyte infiltration.

Statistical Analysis.
Statistical analyses were performed using Student’s t test and the {chi}2 test; Ps <0.05 were regarded as statistically significant. EXCEL and Statistica softwares were used for analyses. All of the experiments were performed at least three times.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Peptide Mimic of GlcNAc Moiety.
It has become evident that both CD4+ and CD8+ T cells can recognize glycopeptides carrying mono- and disaccharides in a MHC-restricted manner provided the glycan group is attached to the peptide at suitable positions (13) . Reactivity patterns of lectins with Meth A cells indicate that GlcNAc glycosyl epitopes are more highly expressed on Meth A tumor cells than the T antigen Galß1–3 N-acetylgalactosamine epitope, because WGA displays greater reactivity with Meth A cells than peanut agglutinin (Fig. 1, A and B)Citation . WGA binds to the peptide 106 mimotope in a concentration-dependent manner as assessed by ELISA (Fig. 1C)Citation . This binding is selectively and significantly inhibitible by WGA-reactive GlcNAc in a concentration-dependent manner (Fig. 1D)Citation , further indicating that the peptide mimotope is reactive with the GlcNAc-binding site of WGA, and, therefore, peptide 106 is an effective antigenic mimic of GlcNAc.



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  		Fig. 1. Binding of wheat germ agglutinin (WGA) to the peptide and Meth A cells and the inhibition of WGA binding to the peptide. Meth A cells were incubated with biotinylated peanut agglutinin (A) or WGA (B) and were washed and stained with streptavidin-FITC for fluorescence-activated cell sorting (FACS) assay. Continuous and broken lines show streptavidin-FITC and lectins plus streptavidin-FITC, respectively. C, 96-well ELISA plates were coated with the peptide (50 µg/ml) and were incubated with biotinylated WGA; after washing, the plate binding was visualized by adding streptavidin-horseradish peroxidase. D, inhibition of binding of WGA to the peptide was performed by competitive carbohydrate N-acetylglucosamine (GlcNAc). N-acetylgalactosamine (GalNac) was used as a negative control. WGA was preincubated with serial dilutions of carbohydrates overnight at +4°C and then added to peptide-coated plates as above. Results present the mean value ± SD. *, P < 0.05; **, P < 0.01. ***, P < 0.0005, as compared with the inhibition of GalNac at the same concentration.

 
Therapeutic Peptide Immunization Induces Tumor Regression.
To study the outcome of peptide immunization on the growth of solid tumors in vivo, we evaluated the antitumor effect of the peptide 106 on established Meth A tumors. BALB/c females were inoculated s.c. with Meth A cells, and 7 days later, treatment was started with the peptide. As shown in Fig. 2ACitation , immunization moderately affected the growth of Meth A sarcoma, because 6 mice of 11 immunized were cured ({chi}2 test, P = 0.01, as compared with animals that were given IL-12 only). Fig. 2BCitation demonstrates that treatment of animals with IL-12 after peptide immunization tended to enhance the immune response and was successful in mediating complete eradication of established tumors ({chi}2 test, P = 0.008, as compared with peptide-immunized only). Treatment of tumor-bearing mice with only IL-12 did not affect tumor growth (Fig. 2C)Citation in keeping with other such studies (14) .



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  		Fig. 2. Effect of peptide immunization on Meth A tumor growth and regression. BALB/c female mice were inoculated s.c. with 5 x 105 Meth A cells on day 0. A and B, 7 days after tumor inoculation peptide immunization started, mice were immunized i.p. with 106 multiple-antigen peptide/QS21 three times. Interleukin 12 was administered alone (C) or after peptide immunization (B) at indicated doses daily for 5 days, starting on the day of the last peptide immunization. Tumor growth is expressed as the mean diameter for each individual mouse. P ac and P ba, Ps of {chi}2 tests comparing A with C and B with A, respectively.

 
We further determined that peptide/IL-12 combination therapy is highly effective even at lower doses of IL-12, because 100 ng of daily IL-12 treatment in the combined therapy, but not alone ({chi}2 test, P = 001), eradicated tumors in five mice of five challenged (Fig. 3, A and B)Citation . The time of the beginning of immunization and the size of tumor at the time of immunization affect the efficacy of immunization. When immunizations were started at day 14 or later or when treating tumors with a mean diameter larger than 7 mm, the efficacy of immunization dropped (Fig. 3C)Citation , ruling out the possible effect of hyperimmunization per se on the outcome of the challenge experiments. To further rule out nonspecific effects of hyperimmunization, we observed that cell-based vaccination using 106 mitomycin-C-inactivated Meth A cells, followed by IL-12 administration, also failed to induce tumor regression (Fig. 3D)Citation . This latter result confirmed a previous study in which Meth A immunization along with IL-12 failed to induce tumor regression (14) . Our results are in agreement with other therapeutic vaccine studies on Meth A cells, in which enhancement of antitumor T-cell responses led to quick eradication of established tumors (15 , 16) .



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  		Fig. 3. Effect of late peptide or cell immunizations on the growth of the tumor. Tumor was established as explained in legend to Fig. 2Citation . A and B, the same immunization as performed in Fig. 2Citation but with lower doses of interleukin (IL)-12.C, peptide immunization was started 14 days after tumor inoculation.D, 7 days after tumor inoculation, mice were immunized i.p. with 106 mitomycin-C-inactivated Meth A tumor cells for three times at 4–5-day intervals. IL-12 was administered alone (B), after peptide immunization (A and C), or after cell immunization (D) at indicated doses daily for 5 days, starting on the day of last peptide or cell immunization. P ab(d), the P of {chi}2 test comparing A with B or D.

 
Adoptive Transfer of Splenocytes Stimulates Eradication of Tumors in Nude Mice.
To further assess whether the antitumor activity mediated by peptide/IL-12 therapy is T-cell dependent, we evaluated our therapeutic strategy in nude mice. BALB/c-nu/nu mice bearing Meth A tumors were immunized with the peptide followed by IL-12 treatment. Combined peptide/IL-12 therapy had no effect on tumor growth of nude mice, indicating the dependence of mediated tumor regression on T cells (data not shown). Next, nude mice were transplanted with Meth A cells and were give injections i.p. of fresh splenocytes, isolated from cured mice, 10 days later (Fig. 4)Citation . Immune cells transferred had a dramatic effect on tumor size because by day 15 after transfer, tumor was eradicated completely in all four mice tested ({chi}2 test, P = 0.005).



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  		Fig. 4. Adoptive transfer of fresh immune splenocytes eradicated established tumors in nude mice. Two groups (four per group) of nude mice were inoculated s.c. with 5 x 105 Meth A cells into the right flank. Ten days after inoculation when average of tumors diameter was about 7 mm, one group was given injections i.p. of 1.5 x 107 of fresh splenocytes collected from already immunized and cured BALB/c animals. Splenocytes were prepared by lysis of erythrocytes and consequent washing several times with fresh medium. Pictures shown are taken from a representative individual on the day of cell transfer (A), 7 days later (B), 12 days later (C), and 17 days later (D). E, tumor size in control group 25 days after transplant as one representative individual of four is shown. F, average of tumor diameter for four mice per group in naïve control ({bullet}) and splenocyte-transferred groups ({blacksquare}). Arrow, the date of injection of splenocytes.

 
In a follow-up study, splenocytes were depleted of B cells and enriched for CD4+ or CD8+ cells, in vitro, and then were transferred to tumor-bearing nude mice. Our data indicate that CD8+ cells are required for efficient eradication of tumor; however, the process seems dependent on both CD4+ and CD8+ cells (Fig. 5)Citation . Histological sections of tumor sites and surrounding tissues were prepared (Fig. 6)Citation . Contrary to nonimmunized tumor-bearing mice, we detected lymphocytes around the periphery and infiltrating into tumor mass of immunized mice (Fig. 6, A and B)Citation . Staining of sections obtained from the tumor site of a cured mouse shows the presence of lymphocytes, although no tumor is detectable microscopically (Fig. 6C)Citation .



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  		Fig. 5. CD8+ T cells are required for successful adoptive therapy of established tumors. Solid tumors were established in nude mice, and at day 7, enriched splenocytes were transferred i.p. For enrichment, splenocytes were passed through nylon wool after which the percentage of CD19+ cells that remained were less than 7%. The percentage of CD8+ and CD4+ cells in CD4 and CD8-enriched population was less than 10%. Results present the mean value ± SD. *, P < 0.05; **, P < 0.01. ***, P < 0.0005, as compared with mean tumor diameter of CD4+ -transferred animals.

 


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  		Fig. 6. Lymphocytes infiltrate the Meth A challenge site in immunized mice. Fixed sections from tumor site of nonimmunized tumor-bearing mice (A), immunized tumor-shrinking mice (B), and immunized tumor-eliminated mice (C) stained with H&E. Mice were transplanted, and immunization started 7 days later. Samples were obtained when tumor was 16 mm (A) and 2 mm (B) and at 5 days after tumor eradication (C).

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Carbohydrates are abundantly expressed on the surface of malignant cells, and induction and enhancement of a cell-mediated immune response toward these antigens has outstanding implications in vaccination for and treatment of cancer. T-cell recognition of nonpeptidic and modified peptide antigens is, however, still poorly understood. Peptide mimetics of carbohydrate antigens can activate peptide-specific cellular responses, but they have also been shown to activate cellular responses that might be cross-reactive with carbohydrate moieties (12 , 17) . The induction of carbohydrate-reactive T–lymphocytes with peptide mimics is based on a functional definition of T-cell mimotopes. One possible explanation is that the peptide mimotope activates cross-reactive CTLs that recognize a processed O-linked glycopeptide associated with MHC class I. It is also possible to generate carbohydrate-specific unrestricted CTL responses with MHC class I-binding carrier peptides (18) . However, we previously showed that anti-MHC Class I antibody blocks CTL killing of Meth A cells in vitro by T cells derived from peptide 106 immunized mice (12) .

Immunization with cells in combination with IL-12 had no obvious enhancement of antitumor immune effects. Our data propose that replacing cell immunization with peptide 106 enhanced a potential immune responses resulting in a significant but moderate tumor eradication. Further treatment of peptide-immunized mice with IL-12 helped significantly in stimulating eradication of established tumor in all of the animals tested. Lack of tumor shrinkage on cell-based immunization rules out the possibility that hyperimmunization had a bearing on tumor regression. Taken together, these results indicate that peptide immunization enables an effective antitumor immune response, the potential of which can be significantly enhanced with IL-12 administration. Other groups have performed therapeutic immunization on Meth A cells by immunization with p53 mutant epitope, starting the immunizations 7 days after tumor inoculations, and have demonstrated an efficient enhancement of antitumor cellular immune responses leading to eradication of tumor mass in the majority of animals within 2 weeks after the first immunization (15 , 16) . Our findings are in concert with the results of these studies.

Because resting T cells do not express the IL-12 receptor (19) and IL-12 responsiveness is only activated after T-cell receptor stimulation (20) , we observed that purified peptide-specific T cells were stimulated with IL-12 in vitro (data not shown). IL-12 treatment is ineffective in the Meth A tumor model (14) as further observed in our studies. Because IL-12 responsiveness of T cells is induced after T-cell receptor stimulation, the lack of IL-12 responsiveness suggests that T cells in Meth A-bearing mice are not sensitized to Meth A tumor antigen on immunization with Meth A cells. In contrast, our data suggest that peptide immunization can sensitize tumor-reactive T cells that are responsive to IL-12. It is possible that peptide immunization further expands B and T cells that have been primed via shed glycoprotein(s) processing. We propose that peptide 106 immunization activated a population of Th1 and CTLs with production of IFN{gamma} (12) , and in vivo IL-12 treatment further helps to expand the T-cell population and IFN{gamma} production. In previous studies, the failure of IL-12 treatment to induce tumor regression was also considered to be associated with the lack of T-cell migration to tumor sites (14) . It was argued that sensitization of T cells to tumor antigens and generation of IL-12 responsiveness are insufficient to induce tumor regression when sensitized T cells are not allowed to migrate to tumor sites. In our studies, we observe lymphocyte migration to tumor sites.

In summary, this work further postulates the occurrence of saccharide epitopes for T cells linked to peptides with anchoring motifs for MHC Class I (6 , 13) . Although analogous to the haptens trinitrophenyl and O-ß-linked acetyl-glucosamine, the potential implications of natural carbohydrates as antigenic epitopes for CTL in biology are considerable and are understudied. Consequently, it might be possible for peptide mimetics to activate T cells that recognize carbohydrate moieties on native glycopeptides (21) . Peptides that mimic carbohydrate structures attached to class I or class II anchoring peptides would extend our notion of vaccine design for cancer immunotherapy in the adjuvant setting.


   ACKNOWLEDGMENTS
 
We thank Charlotte Read Kensil of Antigenics Inc. (Framingham, MA) for the QS-21. We thank Eric Siegel of the department of Biometry, University of Arkansas for Medical Sciences, for advise on the statistical analysis.


   FOOTNOTES
 
Grant support: NIH Grant CA089480 and Department of Defense Grant DAMD17-0101-0366.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Thomas Kieber-Emmons, Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, 4301 West Markham Street slot 824, Little Rock, AR 72205. Phone: (501) 526-5930; Fax: (501) 526-5934; E-mail: tke{at}uams.edu

Received 5/28/03. Revised 10/ 2/03. Accepted 1/ 7/04.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Danishefsky SJ, Allen JR From the laboratory to the clinic: a retrospective on fully synthetic carbohydrate-based anticancer vaccines [frequently used abbreviations are listed in the appendix]. Angew Chem Int Ed Engl, 39: 836-63, 2000.[CrossRef][Medline]
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