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01-12-2011 | Original article

Regulatory T-cell depletion synergizes with gp96-mediated cellular responses and antitumor activity

Authors: Xiaoli Yan, Xiaojun Zhang, Yanzhong Wang, Xinghui Li, Saifeng Wang, Bao Zhao, Yang Li, Ying Ju, Lizhao Chen, Wenjun Liu, Songdong Meng

Published in: Cancer Immunology, Immunotherapy | Issue 12/2011

Abstract

Despite its potent immunostimulatory properties, vaccination with autologous tumor-derived gp96 has relatively modest antitumor effect in a range of clinical trials. Based on our previous study showing a gp96-mediated immune balance between CTL and Tregs, here we investigated possible synergy between gp96 vaccine and systemic Treg depletion on induction of antitumor T-cell immunity and the mechanisms accounting for synergistic efficacy. In gp96–peptide complex immunized BALB/c mice, anti-CD25 mAb treatment significantly increased IFN-γ-producing CD8⁺ and CD4⁺ T cells by about 1–2-fold in spleen and 40–50% in lymph node. A significantly higher number of peptide-specific CTL were observed under anti-CD25 mAb treatment compared with no treatment. Moreover, Treg depletion synergistically improved the anticancer activity of tumor-derived gp96 vaccine in the poorly immunogenic and highly tumorigenic B16 melanoma model in C57BL/6 J mice. While gp96 immunization alone led to the modest enhancement of CTL activities in spleen, the combination with Treg depletion dramatically increased tumor-specific CTL responses. In addition, the combination resulted in a significant increase of CD8⁺ T-cell infiltration in tumor, which correlated with an enhanced inhibition of tumor growth. Our results provide evidence that targeting Tregs may provide a more efficient strategy to potentiate gp96-mediated T-cell responses and enhance the antitumor efficiency of gp96-based therapeutic vaccine.

Srivastava PK, Udono H, Blachere NE et al (1994) Heat shock proteins transfer peptides during antigen processing and CTL priming. Immunogenetics 39:93–98PubMedCrossRef

Ishii T, Udono H, Yamano T et al (1999) Isolation of MHC class I-restricted tumor antigen peptide and its precursors associated with heat shock proteins hsp70, hsp90, and gp96. J Immunol 162:1303–1309PubMed

Kropp LE, Garg M, Binder RJ (2010) Ovalbumin-derived precursor peptides are transferred sequentially from gp96 and calreticulin to MHC class I in the endoplasmic reticulum. J Immunol 184:5619–5627PubMedCrossRef

Srivastava PK, DeLeo AB, Old LJ (1986) Tumor rejection antigens of chemically induced sarcomas of inbred mice. Proc Natl Acad Sci USA 83:3407–3411PubMedCrossRef

Tamura Y, Peng P, Liu K et al (1997) Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations. Science 278:117–120PubMedCrossRef

Blachere NE, Li Z, Chandawarkar RY et al (1997) Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J Exp Med 186:1315–1322PubMedCrossRef

Doody AD, Kovalchin JT, Mihalyo MA et al (2004) Glycoprotein 96 can chaperone both MHC class I- and class II-restricted epitopes for in vivo presentation, but selectively primes CD8+ T cell effector function. J Immunol 172:6087–6092PubMed

Binder RJ, Srivastava PK (2004) Essential role of CD91 in re-presentation of gp96-chaperoned peptides. Proc Natl Acad Sci USA 101:6128–6133PubMedCrossRef

Matsutake T, Sawamura T, Srivastava PK (2010) High efficiency CD91- and LOX-1-mediated re-presentation of gp96-chaperoned peptides by MHC II molecules. Cancer Immun 10:7–14PubMed

10.

Akutsu Y, Matsubara H, Urashima T et al (2007) Combination of direct intratumoral administration of dendritic cells and irradiation induces strong systemic antitumor effect mediated by GRP94/gp96 against squamous cell carcinoma in mice. Int J Oncol 31:509–515PubMed

11.

Warger T, Hilf N, Rechtsteiner G et al (2006) Interaction of TLR2 and TLR4 ligands with the N-terminal domain of Gp96 amplifies innate and adaptive immune responses. J Biol Chem 281:22545–22553PubMedCrossRef

12.

Yang Y, Liu B, Dai J et al (2007) Heat shock protein gp96 is a master chaperone for toll-like receptors and is important in the innate function of macrophages. Immunity 26:215–226PubMedCrossRef

13.

McGettrick AF, O’Neill LA (2010) Localisation and trafficking of Toll-like receptors: an important mode of regulation. Curr Opin Immunol 22:20–27PubMedCrossRef

14.

Jockheck-Clark AR, Bowers EV, Totonchy MB et al (2010) Re-examination of CD91 function in GRP94 (glycoprotein 96) surface binding, uptake, and peptide cross-presentation. J Immunol 185:6819–6830PubMedCrossRef

15.

Lev A, Dimberu P, Das SR et al (2009) Efficient cross-priming of antiviral CD8+ T cells by antigen donor cells is GRP94 independent. J Immunol 183:4205–4210PubMedCrossRef

16.

Pilla L, Patuzzo R, Rivoltini L et al (2006) A phase II trial of vaccination with autologous, tumor-derived heat-shock protein peptide complexes Gp96, in combination with GM-CSF and interferon-alpha in metastatic melanoma patients. Cancer Immunol Immunother 55:958–968PubMedCrossRef

17.

Testori A, Richards J, Whitman E et al (2008) Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician’s choice of treatment for stage IV melanoma: the C-100–21 Study Group. J Clin Oncol 26:955–962PubMedCrossRef

18.

Belli F, Testori A, Rivoltini L et al (2002) Vaccination of metastatic melanoma patients with autologous tumor-derived heat shock protein gp96-peptide complexes: clinical and immunologic findings. J Clin Oncol 20:4169–4180PubMedCrossRef

19.

Wood CG, Srivastava P, Lacombe L et al (2009) Survival update from a multicenter, randomized, phase III trial of vitespen versus observation as adjuvant therapy for renal cell carcinoma in patients at high risk of recurrence. J Clin Oncol 27:15s-abstr 3009

20.

Parsa A, Crane C, Han S et al (2011) Autologous heat shock protein vaccine (HSPPC-96) for patients with recurrent glioblastoma (GBM): results of a phase II multicenter clinical trial with immunological assessments. J Clin Oncol 29:abstr 2565

21.

Wood CG, Mulders P (2009) Vitespen: a preclinical and clinical review. Future Oncol 5:763–774PubMedCrossRef

22.

Aalamian M, Fuchs E, Gupta R et al (2006) Autologous renal cell cancer vaccines using heat shock protein-peptide complexes. Urol Oncol 24:425–433PubMedCrossRef

23.

Buckwalter MR, Srivastava PK (2008) “It is the antigen(s), stupid” and other lessons from over a decade of vaccitherapy of human cancer. Semin Immunol 20:296–300PubMedCrossRef

24.

Maki RG, Livingston PO, Lewis JJ et al (2007) A phase I pilot study of autologous heat shock protein vaccine HSPPC-96 in patients with resected pancreatic adenocarcinoma. Dig Dis Sci 52:1964–1972PubMedCrossRef

25.

Alatrakchi N, Koziel M (2009) Regulatory T cells and viral liver disease. J Viral Hepat 16:223–229PubMedCrossRef

26.

Elkord E, Alcantar-Orozco EM, Dovedi SJ et al (2010) T regulatory cells in cancer: recent advances and therapeutic potential. Expert Opin Biol Ther 10:1573–1586PubMedCrossRef

27.

Shimizu J, Yamazaki S, Sakaguchi S (1999) Induction of tumor immunity by removing CD25+ CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163:5211–5218PubMed

28.

Kimpfler S, Sevko A, Ring S et al (2009) Skin melanoma development in ret transgenic mice despite the depletion of CD25⁺Foxp3⁺ regulatory T cells in lymphoid organs. J Immunol 183:6330–6337PubMedCrossRef

29.

Chandawarkar RY, Wagh MS, Srivastava PK (1999) The dual nature of specific immunological activity of tumor-derived gp96 preparations. J Exp Med 189:1437–1442PubMedCrossRef

30.

Chandawarkar RY, Wagh MS, Kovalchin JT et al (2004) Immune modulation with high-dose heat-shock protein gp96: therapy of murine autoimmune diabetes and encephalomyelitis. Int Immunol 16:615–624PubMedCrossRef

31.

Li H, Zhou M, Han J et al (2005) Generation of murine CTL by a hepatitis B virus-specific peptide and evaluation of the adjuvant effect of heat shock protein glycoprotein 96 and its terminal fragments. J Immunol 174:195–204PubMed

32.

Dai J, Liu B, Ngoi SM et al (2007) TLR4 hyperresponsiveness via cell surface expression of heat shock protein gp96 potentiates suppressive function of regulatory T cells. J Immunol 178:3219–3225PubMed

33.

Liu Z, Li X, Qiu L et al (2009) Treg suppress CTL responses upon immunization with HSP gp96. Eur J Immunol 39:3110–3120PubMedCrossRef

34.

Meng SD, Gao T, Gao GF et al (2001) HBV-specific peptide associated with heat-shock protein gp96. Lancet 357:528–529PubMedCrossRef

35.

Meng SD, Song J, Rao Z et al (2002) Three-step purification of gp96 from human liver tumor tissues suitable for isolation of gp96-bound peptides. J Immunol Methods 264:29–35PubMedCrossRef

36.

Cohen AD, Schaer DA, Liu C et al (2010) Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS One 5:e10436–e10447PubMedCrossRef

37.

Jedema I, van der Werff NM, Barge RM et al (2004) New CFSE-based assay to determine susceptibility to lysis by cytotoxic T cells of leukemic precursor cells within a heterogeneous target cell population. Blood 103:2677–2682PubMedCrossRef

38.

Chou TC, Talalay P (1983) Analysis of combined drug effects—a new look at a very old problem. Trends Pharmacol Sci 4:450–454CrossRef

39.

Lee CH, Chiang YH, Chang SE et al (2009) Tumor-localized ligation of CD3 and CD28 with systemic regulatory T-cell depletion induces potent innate and adaptive antitumor responses. Clin Cancer Res 15:2756–2766PubMedCrossRef

40.

Wang XY, Arnouk H, Chen X et al (2006) Extracellular targeting of endoplasmic reticulum chaperone glucose-regulated protein 170 enhances tumor immunity to a poorly immunogenic melanoma. J Immunol 177:1543–1551PubMed

41.

Srivastava PK, Das MR (1984) The serologically unique cell surface antigen of Zajdela ascitic hepatoma is also its tumor-associated transplantation antigen. Int J Cancer 33:417–422PubMedCrossRef

42.

Manigold T, Racanelli V (2007) T-cell regulation by CD4 regulatory T cells during hepatitis B and C virus infections: facts and controversies. Lancet Infect Dis 7:804–813PubMedCrossRef

43.

Setiady YY, Coccia JA, Park PU (2010) In vivo depletion of CD4⁺FOXP3⁺ Treg cells by the PC61 anti-CD25 monoclonal antibody is mediated by FcgammaRIII+ phagocytes. Eur J Immunol 40:780–786PubMedCrossRef

44.

Jacobs C, Duewell P, Heckelsmiller K et al (2011) An ISCOM vaccine combined with a TLR9 agonist breaks immune evasion mediated by regulatory T cells in an orthotopic model of pancreatic carcinoma. Int J Cancer 128:897–907PubMedCrossRef

45.

Whelan MC, Casey G, MacConmara M et al (2010) Effective immunotherapy of weakly immunogenic solid tumours using a combined immunogene therapy and regulatory T-cell inactivation. Cancer Gene Ther 17:501–511PubMedCrossRef

46.

Medina-Echeverz J, Fioravanti J, Zabala M et al (2011) Successful colon cancer eradication after chemoimmunotherapy is associated with profound phenotypic change of intratumoral myeloid cells. J Immunol 186:807–815PubMedCrossRef

47.

Mitsui J, Nishikawa H, Muraoka D et al (2010) Two distinct mechanisms of augmented antitumor activity by modulation of immunostimulatory/inhibitory signals. Clin Cancer Res 16:2781–2791PubMedCrossRef

48.

Akins EJ, Moore ML, Tang S et al (2010) In situ vaccination combined with androgen ablation and regulatory T-cell depletion reduces castration-resistant tumor burden in prostate-specific pten knockout mice. Cancer Res 70:3473–3482PubMedCrossRef

49.

Terabe M, Ambrosino E, Takaku S et al (2009) Synergistic enhancement of CD8+ T cell-mediated tumor vaccine efficacy by an anti-transforming growth factor-beta monoclonal antibody. Clin Cancer Res 15:6560–6569PubMedCrossRef

50.

Rech AJ, Vonderheide RH (2009) Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells. Ann N Y Acad Sci 1174:99–106PubMedCrossRef

51.

Jacobs JF, Punt CJ, Lesterhuis WJ et al (2010) Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: a phase I/II study in metastatic melanoma patients. Clin Cancer Res 16:5067–5078PubMedCrossRef

52.

Li X, Kostareli E, Suffner J et al (2010) Efficient Treg depletion induces T-cell infiltration and rejection of large tumors. Eur J Immunol 40:3325–3335PubMedCrossRef

53.

Vendetti S, Davidson TS, Veglia F et al (2010) Polyclonal Treg cells enhance the activity of a mucosal adjuvant. Immunol Cell Biol 88:698–706PubMedCrossRef

54.

B Van’t Land, Schijf M, van Esch BC et al (2010) Regulatory T-cells have a prominent role in the immune modulated vaccine response by specific oligosaccharides. Vaccine 28:5711–5717CrossRef

55.

Di Paolo NC, Tuve S, Ni S et al (2006) Effect of adenovirus-mediated heat shock protein expression and oncolysis in combination with low-dose cyclophosphamide treatment on antitumor immune responses. Cancer Res 66:960–969PubMedCrossRef

56.

Schreiber TH, Deyev VV, Rosenblatt JD et al (2009) Tumor-induced suppression of CTL expansion and subjugation by gp96-Ig vaccination. Cancer Res 69:2026–2033PubMedCrossRef

57.

Wang S, Qiu L, Liu G et al (2011) Heat shock protein gp96 enhances humoral and T cell responses, decreases Treg frequency and potentiates the anti-HBV activity in BALB/c and transgenic mice. Vaccine. doi:10.1016/j.vaccine.2011.1005.1008

Title: Regulatory T-cell depletion synergizes with gp96-mediated cellular responses and antitumor activity
Authors: Xiaoli Yan
Xiaojun Zhang
Yanzhong Wang
Xinghui Li
Saifeng Wang
Bao Zhao
Yang Li
Ying Ju
Lizhao Chen
Wenjun Liu
Songdong Meng
Publication date: 01-12-2011
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 12/2011
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-011-1076-5

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