Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models

Xinmei Zhu, Fumihiko Nishimura, Kotaro Sasaki, Mitsugu Fujita, Jill E Dusak, Junichi Eguchi, Wendy Fellows-Mayle, Walter J Storkus, Paul R Walker, Andres M Salazar, Hideho Okada, Xinmei Zhu, Fumihiko Nishimura, Kotaro Sasaki, Mitsugu Fujita, Jill E Dusak, Junichi Eguchi, Wendy Fellows-Mayle, Walter J Storkus, Paul R Walker, Andres M Salazar, Hideho Okada

Abstract

Background: Toll-like receptor (TLR)3 ligands serve as natural inducers of pro-inflammatory cytokines capable of promoting Type-1 adaptive immunity, and TLR3 is abundantly expressed by cells within the central nervous system (CNS). To improve the efficacy of vaccine strategies directed against CNS tumors, we evaluated whether administration of a TLR3 ligand, polyinosinic-polycytidylic (poly-IC) stabilized with poly-lysine and carboxymethylcellulose (poly-ICLC) would enhance the anti-CNS tumor effectiveness of tumor peptide-based vaccinations.

Methods: C57BL/6 mice bearing syngeneic CNS GL261 glioma or M05 melanoma received subcutaneous (s.c.) vaccinations with synthetic peptides encoding CTL epitopes--mEphA2 (671-679), hgp100 (25-33) and mTRP-2 (180-188) for GL261, or ovalbumin (OVA: 257-264) for M05. The mice also received intramuscular (i.m.) injections with poly-ICLC.

Results: The combination of subcutaneous (s.c.) peptide-based vaccination and i.m. poly-ICLC administration promoted systemic induction of antigen (Ag)-specific Type-1 CTLs expressing very late activation antigen (VLA)-4, which confers efficient CNS-tumor homing of vaccine-induced CTLs based on experiments with monoclonal antibody (mAb)-mediated blockade of VLA-4. In addition, the combination treatment allowed expression of IFN-gamma by CNS tumor-infiltrating CTLs, and improved the survival of tumor bearing mice in the absence of detectable autoimmunity.

Conclusion: These data suggest that poly-ICLC, which has been previously evaluated in clinical trials, can be effectively combined with tumor Ag-specific vaccine strategies, thereby providing a greater index of therapeutic efficacy.

Figures

Figure 1
Figure 1
High-level expression of EphA2 is restricted to GL261 glioma in the mouse brain. Paraffin embedded tissue sections prepared from the brains of C57BL/6 mice bearing day 14 GL261 glioma in the right frontal lobe were stained with anti-EphA2 monoclonal antibody (C-20 Ab; Santa Cruz Biotechnology, Inc). After washing, sections were incubated with biotinylated goat anti-rabbit IgG (Vector Laboratories), followed by avidin-biotin-complex peroxidase (Vectastain ABC kits; Vector Laboratories). Reaction products were developed using a Nova Red substrate kit (Vector Laboratories) giving rise to red-brown deposits. The sections were also counter-stained with hematoxylin (blue). The letter "T" in the figure indicates tumor tissue, with the letter "N" in the figure indicating normal brain tissue. Original magnification; × 20.
Figure 2
Figure 2
Poly-ICLC administration enhances vaccine-induced specific CTL generation in vivo. (A), C57BL/6 mice received OVA-vaccines with or without i.m. poly-ICLC on days 0 and 7 (n = 3/group). OVA-specific CD8+ T cell activities in SPC (a) and draining inguinal LN cells (b) were evaluated by in vivo CTL assays on day 14. *P < 0.01 for the combination group compared with poly-ICLC alone or control group; and P < 0.05 for the combination group compared with vaccine alone group. #P > 0.05 for the group receiving vaccine alone compared with poly-ICLC alone or control group. (B), C57BL/6 mice received GAA-vaccines with or without i.m. poly-ICLC on days 0 and 7. SPCs were harvested on day 14. Following a 5-day in vitro stimulation with 20 IU/ml IL-2 and three GAA peptides, SPCs were tested for their lytic activity against GL261 glioma cells (a) or EL4 cells (b) in a 4-hr standard 51Cr-release assay. (C), C57BL/6 mice received EphA2-vaccines with or without i.m. poly-ICLC on days 0 and 7. On day 14, SPC were harvested, in vitro stimulated with low-dose (20 IU/ml) hIL-2 and mEphA2671–679 for 5 days prior to performance of mouse IFN-γ specific ELISA using culture-supernatants. *P < 0.001 compared to vaccine alone, poly-ICLC alone and the control groups. For (A-C), n = 3/group, and data represent results from one of 3 independent experiments performed with similar results obtained. Error bars represent standard deviation (SD).
Figure 3
Figure 3
Poly-ICLC administration promotes the infiltration of Type-1 Ag-specific T cells into CNS rumor sites. (A-C), mice bearing day 10 M05 tumors were immunized with either: OVA257–264vaccines plus poly-ICLC, OVA257–264 vaccines only, mock vaccines plus poly-ICLC, or control mock vaccines on days 10 and 15. In the experiments depicted in (A-b, B-b, C), mice also received i.v. injections of 5 × 106 OT-I mice-derived naïve SPCs and LN cells on day 10 prior to the first immunization. On day 16, the mice were sacrificed, and BILs from tumor-bearing hemisphere were analyzed for the presence of OVA257–264-specific T-cells using TC-labeled anti-mouse CD3 mAb and PE-labeled OVA257–264-specific tetramer. N = 5 mice/group. BILs from the same group were pooled and compared between groups. (A), numbers represent the percentage of CD3+/OVA tetramer+ cells in lymphocyte-gated BILs. (B), total numbers of CD3+/OVA tetramer+ BILs per mouse with (b) or without (a) adoptive transfer of naïve OT-1 mouse-derived SPCs and LN cells. (C), expression of IFN-γ by isolated BILs (a), SPCs (b), ipsilateral inguinal (c), and cervical (d) LN cells. Aliquots of 1.0 × 106/ml isolated lymphocytes were cultured with 5 μg/ml OVA257–264 and 20 IU/ml rhIL-2 for 6 h (BILs) or 5 days (for SPCs and LN cells), and IFN-γ in the supernatant was measured by specific ELISA. For BILs (a), *P < 0.05 compared to all other groups. For SPCs (b), *P < 0.001 compared to all other groups. For iLNs (c) and cLNs (d), *P < 0.001 for the combination group compared to all other groups, #P < 0.01, for the vaccine alone group compared to the control or the poly-ICLC alone group. Columns, mean of three wells in 96 well plate; Error bars, SD. Representative of 2 and 4 independent experiments with similar results, for (a) and (b), respectively.
Figure 4
Figure 4
Poly-ICLC enhances the T-cell expression of α4-integrin (CD49d), which confers efficient CNS-tumor homing of Ag-specific T-cells. (A and B), C57BL/6 mice bearing day 10 i.c. M05 tumors received 5 × 10 6 naive OT-1 mouse-derived T-cells, then OVA-vaccines and/or poly-ICLC administrations on days 10 and 15. BILs (A) and SPCs (B) were harvested on day 16, and evaluated for the α4-integrin expression on CD8+, OVA-tetramer+ cells by flow cytometry. (A), numbers represent the percentage of α4-integrin+/CD8+ (upper panel), α4-integrin+/OVA+ cells (lower panel) in lymphocyte-gated BIL populations. (B), numbers represent the percentage of α4-integrin+/OVA+ cells in lymphocyte-gated SPC populations. (C), C57BL/6 mice bearing day 15 i.c. GL261 tumors received 5 × 10 6 naive Pmel-1 mouse-derived T cells, then hgp100-vaccines and/or poly-ICLC administrations on days 15 and 20. BILs were harvested on day 21, and evaluated for the α4-integrin expression on CD8+/TCRvβ13+ cells by flow cytometry. Numbers represent the percentage of α4-integrin+/TCRvβ13+ T-cells in lymphocyte-gated populations. (D and E), mAb-mediated blockade of α4-integrin inhibited the CNS-tumor infiltration of OVA-specific T-cells, while not depleting Ag-reactive T-cells systemically. C57BL/6 mice bearing day 10 i.c. M05 tumors received i.p. injections of anti-α 4-integrin mAbs (R1-2, 150 μg/mouse and 9C10, 150 μg/mouse), or control isotype mAb (rat IgG2bK, clone, A95-1, 300 μg/mouse) at 2 hrs before i.v. adoptive transfer of 5 × 106 naïve OT-1 mouse-derived T-cells and subsequent OVA-vaccination and poly-ICLC administration. On day 13, the mice received the 2nd OVA-vaccination and poly-ICLC administration at 2 hrs following the 2nd i.p. mAb injections. BILs, SPC and lymphocytes from draining inguinal (i)LNs were harvested on day 16. Numbers of CD3+/OVA tetramer+ BILs per mouse (D), and the presence of CD8+, OVA-tetramer reactive T cells in iLN and SPC are depicted (E). Data are representative of 3 independent experiments with similar results.
Figure 5
Figure 5
GAA-vaccines in combination with i.m. poly-ICLC administrations induce long-term anti-GL261 protective immunity. (A), C57BL/6 mice received s.c. GAA-vaccines with or without i.m. poly-ICLC on days -14 and -7. On day 0, mice received i.c. inoculations of 1 × 105 GL261 cells, with survival subsequently monitored. **P = 0.003 for the mice receiving combination treatments compared with the control group. *P = 0.0521 for the mice receiving GAA-vaccines alone compared with the control group (Log rank test). (B and C), mice that survived for 90 days following GAA-vaccines and i.m. poly-ICLC or GAA-vaccine alone in (A) were re-challenged with 5 × 104 GL261 in the contralateral hemisphere of the brain (n = 3/group). As controls, naïve mice received the same number of GL261 cells. BILs were harvested from the tumor-bearing hemisphere at 7 days after tumor re-challenge, and stained with TC-anti-CD8 and PE-H-2Kb/TRP2180–188-specific tetramer. (B), numbers represent the percentage of CD8+/TRP-2 tetramer+ cells in lymphocyte-gated BILs in each group. (C), numbers of viable CD8+ BILs per mouse.
Figure 6
Figure 6
H&E and LFB staining of brain sections reveal the absence of pathologic autoimmunity. Perfusion-fixed brains were obtained from GL261-bearing mice treated with GAA-vaccine and poly-ICLC on day 90 after the tumor-inoculation. Frozen sections were stained with LFB (B and D). Cryostat sections were also stained with H&E to evaluate the overall infiltration of mononuclear immune cells (A and C). Images were taken from the basal ganglia. The thick bundle strongly stained with LFB indicates internal capsule. All images were obtained from the corresponding visual fields. The original magnifications are × 10 (for A and B), and × 20 (for C and D). There was no evidence of demyelination, hemorrhage, or pathological immune cell infiltration throughout the brain.
Figure 7
Figure 7
Poly-ICLC administration induces IFN-α in serum of treated mice. Peripheral blood samples were drawn from the tail vein at 0, 12, 24 and 48 hrs following i.m. poly-ICLC (50 μg) treatment. Serum IFN-α levels were determined using specific ELISA (Endogen, Rockford, IL). The average values of 3 mice in treated (■) or non-treated (▲) mice are depicted (n = 3/group). Systemic induction of IFN-α in serum peaked at 24 hrs following the poly-ICLC injection, whereas control mice with no poly-ICLC administration did not display any elevation in IFN-α levels.
Figure 8
Figure 8
Poly-ICLC stimulates GL261 glioma-expression of IFN-beta, TLR3, MHC class I and IP-10. In vitro cultured GL261 cells were treated with or without 50 μg/ml poly-ICLC for 24 hrs, and evaluated for expression of IFN-β in culture-supernatant by specific ELISA (A), surface TLR3 (B) and H-2Kb (C) by flow-cytometry, and for production of IP-10 in culture-supernatant by specific ELISA (D). (B), Dashed thin line: isotype control antibody, Thin line: TLR3 expression without poly-ICLC treatment, Bold line: TLR3 expression in the presence of poly-ICLC. (C), Black thin line: isotype control antibody, Dashed thin line: H-2Kb expression without poly-ICLC treatment, Filled grey area: H-2Kb expression with poly-ICLC treatment and control isotype-IgG, Black thick line: H-2Kb expression with poly-ICLC treatment and neutralizing anti IFN-β mAb.

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