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Open Access 01-12-2019 | Vaccination | Research

A novel method for efficient generation of antigen-specific effector T-cells using dendritic cells transduced with recombinant adeno-associated virus and p38 kinase blockade

Authors: Leonardo Mirandola, Maurizio Chiriva-Internati, Robert Bresalier, Lucia Piccotti, Fabio Grizzi, Francesco M. Marincola

Published in: Journal of Translational Medicine | Issue 1/2019

Abstract

Background

The inefficacy of standard therapeutic strategies for ovarian cancer is reflected by the enduring poor prognosis of this malignancy. Due to the potential for exquisite specificity, sensitivity and long-term memory, immunotherapy offers an alternative modality for durable control of the disease, provided appropriate antigens can be identified and presented in the right context.

Methods

We tested a novel dendritic cell vaccine formulation to reprogram autologous antigen-specific T-cells in vitro, in vivo in a murine model of ovarian cancer, and ex vivo using human cells from patients.

Results

We show that dendritic cells (DCs) treated with a p38 MAPK inhibitor and transduced with a recombinant adenovirus associated vector (AAV) expressing Sperm protein (Sp) 17 are highly effective in generating antigen-specific T-cell cytotoxic response against ovarian cancer cells. Additionally, these DCs enhanced the differentiation of effector T-cells while reducing the frequency of Foxp3⁺ T-reg cells in vitro.

Conclusions

This work provides a rationale for translation of pharmacologically reprogrammed DCs into clinical trials for prevention of tumor recurrence and progression in high-risk ovarian cancer patients.

Chiriva-Internati M, Yu Y, Mirandola L, Jenkins MR, Chapman C, Cannon M, Cobos E, Kast WM. Cancer testis antigen vaccination affords long-term protection in a murine model of ovarian cancer. PLoS ONE. 2010;5:e10471.PubMedPubMedCentralCrossRef

Stumpf M, Hasenburg A, Riener MO, Jutting U, Wang C, Shen Y, Orlowska-Volk M, Fisch P, Wang Z, Gitsch G, et al. Intraepithelial CD8-positive T lymphocytes predict survival for patients with serous stage III ovarian carcinomas: relevance of clonal selection of T lymphocytes. Br J Cancer. 2009;101:1513–21.PubMedPubMedCentralCrossRef

Adams SF, Levine DA, Cadungog MG, Hammond R, Facciabene A, Olvera N, Rubin SC, Boyd J, Gimotty PA, Coukos G. Intraepithelial T cells and tumor proliferation: impact on the benefit from surgical cytoreduction in advanced serous ovarian cancer. Cancer. 2009;115:2891–902.PubMedCrossRef

Cannon MJ, O’Brien TJ. Cellular immunotherapy for ovarian cancer. Expert Opin Biol Ther. 2009;9:677–88.PubMedPubMedCentralCrossRef

Fujita K, Ikarashi H, Takakuwa K, Kodama S, Tokunaga A, Takahashi T, Tanaka K. Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes. Clin Cancer Res. 1995;1:501–7.PubMed

Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, Varela-Rohena A, Haines KM, Heitjan DF, Albelda SM, et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci U S A. 2009;106:3360–5.PubMedPubMedCentralCrossRef

Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10:942–9.PubMedCrossRef

Jackson AM, Mulcahy LA, Zhu XW, O’Donnell D, Patel PM. Tumour-mediated disruption of dendritic cell function: inhibiting the MEK1/2-p44/42 axis restores IL-12 production and Th1-generation. Int J Cancer. 2008;123:623–32.PubMedCrossRef

Jung MY, Son MH, Kim SH, Cho D, Kim TS. IL-32γ induces the maturation of dendritic cells with Th1- and Th17-polarizing ability through enhanced IL-12 and IL-6 production. J Immunol. 2011;6:6.

10.

Xie J, Qian J, Yang J, Wang S, Freeman ME 3rd, Yi Q. Critical roles of Raf/MEK/ERK and PI3K/AKT signaling and inactivation of p38 MAP kinase in the differentiation and survival of monocyte-derived immature dendritic cells. Exp Hematol. 2005;33:564–72.PubMedCrossRef

11.

Wang S, Hong S, Yang J, Qian J, Zhang X, Shpall E, Kwak LW, Yi Q. Optimizing immunotherapy in multiple myeloma: restoring the function of patients’ monocyte-derived dendritic cells by inhibiting p38 or activating MEK/ERK MAPK and neutralizing interleukin-6 in progenitor cells. Blood. 2006;108:4071–7.PubMedPubMedCentralCrossRef

12.

Jarnicki AG, Conroy H, Brereton C, Donnelly G, Toomey D, Walsh K, Sweeney C, Leavy O, Fletcher J, Lavelle EC, et al. Attenuating regulatory T cell induction by TLR agonists through inhibition of p38 MAPK signaling in dendritic cells enhances their efficacy as vaccine adjuvants and cancer immunotherapeutics. J Immunol. 2008;180:3797–806.PubMedCrossRef

13.

Brereton CF, Sutton CE, Lalor SJ, Lavelle EC, Mills KH. Inhibition of ERK MAPK suppresses IL-23- and IL-1-driven IL-17 production and attenuates autoimmune disease. J Immunol. 2009;183:1715–23.PubMedCrossRef

14.

Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S, Huang E, Finlayson E, Simeone D, Welling TH, et al. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood. 2009;114:1141–9.PubMedPubMedCentralCrossRef

15.

Chiriva-Internati M, Wang Z, Salati E, Timmins P, Lim SH. Tumor vaccine for ovarian carcinoma targeting sperm protein 17. Cancer. 2002;94:2447–53.PubMedCrossRef

16.

Chiriva-Internati M, Grizzi F, Weidanz JA, Ferrari R, Yuefei Y, Velez B, Shearer MH, Lowe DB, Frezza EE, Cobos E, et al. A NOD/SCID tumor model for human ovarian cancer that allows tracking of tumor progression through the biomarker Sp17. J Immunol Methods. 2007;321:86–93.PubMedCrossRef

17.

Li FQ, Han YL, Liu Q, Wu B, Huang WB, Zeng SY. Overexpression of human sperm protein 17 increases migration and decreases the chemosensitivity of human epithelial ovarian cancer cells. BMC Cancer. 2009;9:323.PubMedPubMedCentralCrossRef

18.

Chiriva-Internati M, Liu Y, Weidanz JA, Grizzi F, You H, Zhou W, Bumm K, Barlogie B, Mehta JL, Hermonat PL. Testing recombinant adeno-associated virus-gene loading of dendritic cells for generating potent cytotoxic T lymphocytes against a prototype self-antigen, multiple myeloma HM1.24. Blood. 2003;102:3100–7.PubMedCrossRef

19.

Chiriva-Internati M, Liu Y, Salati E, Zhou W, Wang Z, Grizzi F, Roman JJ, Lim SH, Hermonat PL. Efficient generation of cytotoxic T lymphocytes against cervical cancer cells by adeno-associated virus/human papillomavirus type 16 E7 antigen gene transduction into dendritic cells. Eur J Immunol. 2002;32:30–8.PubMedCrossRef

20.

Yu Y, Pilgrim P, Zhou W, Gagliano N, Frezza EE, Jenkins M, Weidanz JA, Lustgarten J, Cannon M, Bumm K, et al. rAAV/Her-2/neu loading of dendritic cells for a potent cellular-mediated MHC class I restricted immune response against ovarian cancer. Viral Immunol. 2008;21:435–42.PubMedCrossRef

21.

Roby KF, Niu F, Rajewski RA, Decedue C, Subramaniam B, Terranova PF. Syngeneic mouse model of epithelial ovarian cancer: effects of nanoparticulate paclitaxel. Nanotax Adv Exp Med Biol. 2008;622:169–81.PubMedCrossRef

22.

Santin AD, Hermonat PL, Ravaggi A, Bellone S, Pecorelli S, Cannon MJ, Parham GP. In vitro induction of tumor-specific human lymphocyte antigen class I-restricted CD8 cytotoxic T lymphocytes by ovarian tumor antigen-pulsed autologous dendritic cells from patients with advanced ovarian cancer. Am J Obstet Gynecol. 2000;183:601–9.PubMedCrossRef

23.

Yu Y, Pilgrim P, Yan J, Zhou W, Jenkins M, Gagliano N, Bumm K, Cannon M, Milzani A, Dalle-Donne I, et al. Protective CD8+ T-cell responses to cytomegalovirus driven by rAAV/GFP/IE1 loading of dendritic cells. J Transl Med. 2008;6:56.PubMedPubMedCentralCrossRef

24.

Santin AD, Hermonat PL, Ravaggi A, Chiriva-Internati M, Zhan D, Pecorelli S, Parham GP, Cannon MJ. Induction of human papillomavirus-specific CD4+ and CD8+ lymphocytes by E7-pulsed autologous dendritic cells in patients with human papillomavirus type 16- and 18-positive cervical cancer. J Virol. 1999;73:5402–10.PubMedPubMedCentral

25.

Cannon MJ, Goyne HE, Stone PJ, Macdonald LJ, James LE, Cobos E, Chiriva-Internati M. Modulation of p38 MAPK signaling enhances dendritic cell activation of human CD4+ Th17 responses to ovarian tumor antigen. Cancer Immunol Immunother. 2013;62:839–49.PubMedPubMedCentralCrossRef

26.

Liu Y, Chiriva-Internati M, Grizzi F, Salati E, Roman JJ, Lim S, Hermonat PL. Rapid induction of cytotoxic T-cell response against cervical cancer cells by human papillomavirus type 16 E6 antigen gene delivery into human dendritic cells by an adeno-associated virus vector. Cancer Gene Ther. 2001;8:948–57.PubMedCrossRef

27.

Mirandola L, Figueroa JA, Phan TT, Grizzi F, Kim M, Rahman RL, Jenkins MR, Cobos E, Jumper C, Alalawi R, Chiriva-Internati M. Novel antigens in non-small cell lung cancer: Sp17, AKAP4, and PTTG1 are potential immunotherapeutic targets. Oncotarget. 2015;6:2812–26.PubMedCrossRef

28.

Chiriva-Internati M, Wang Z, Xue Y, Bumm K, Hahn AB, Lim SH. Sperm protein 17 (Sp17) in multiple myeloma: opportunity for myeloma-specific donor T cell infusion to enhance graft-versus-myeloma effect without increasing graft-versus-host disease risk. Eur J Immunol. 2001;31:2277–83.PubMedCrossRef

29.

Barber A, Zhang T, DeMars LR, Conejo-Garcia J, Roby KF, Sentman CL. Chimeric NKG2D receptor-bearing T cells as immunotherapy for ovarian cancer. Cancer Res. 2007;67:5003–8.PubMedCrossRef

30.

Bondurant KL, Crew MD, Santin AD, O’Brien TJ, Cannon MJ. Definition of an immunogenic region within the ovarian tumor antigen stratum corneum chymotryptic enzyme. Clin Cancer Res. 2005;11:3446–54.PubMedCrossRef

31.

Cannon MJ, O’Brien TJ, Underwood LJ, Crew MD, Bondurant KL, Santin AD. Novel target antigens for dendritic cell-based immunotherapy against ovarian cancer. Expert Rev Anticancer Ther. 2002;2:97–105.PubMedCrossRef

32.

Gupta G, Sharma R, Chattopadhyay TK, Gupta SD, Ralhan R. Clinical significance of sperm protein 17 expression and immunogenicity in esophageal cancer. Int J Cancer. 2007;120:1739–47.PubMedCrossRef

33.

Straughn JM Jr, Shaw DR, Guerrero A, Bhoola SM, Racelis A, Wang Z, Chiriva-Internati M, Grizzle WE, Alvarez RD, Lim SH, Strong TV. Expression of sperm protein 17 (Sp17) in ovarian cancer. Int J Cancer. 2004;108:805–11.PubMedCrossRef

34.

Chiriva-Internati M, Wang Z, Salati E, Wroblewski D, Lim SH. Successful generation of sperm protein 17 (Sp17)-specific cytotoxic T lymphocytes from normal donors: implication for tumour-specific adoptive immunotherapy following allogeneic stem cell transplantation for Sp17-positive multiple myeloma. Scand J Immunol. 2002;56:429–33.PubMedCrossRef

35.

Lim SH, Wang Z, Chiriva-Internati M, Xue Y. Sperm protein 17 is a novel cancer-testis antigen in multiple myeloma. Blood. 2001;97:1508–10.PubMedCrossRef

36.

Bak SP, Walters JJ, Takeya M, Conejo-Garcia JR, Berwin BL. Scavenger receptor-A-targeted leukocyte depletion inhibits peritoneal ovarian tumor progression. Cancer Res. 2007;67:4783–9.PubMedCrossRef

37.

Bamias A, Koutsoukou V, Terpos E, Tsiatas ML, Liakos C, Tsitsilonis O, Rodolakis A, Voulgaris Z, Vlahos G, Papageorgiou T, et al. Correlation of NK T-like CD3+ CD56+ cells and CD4+ CD25+ (hi) regulatory T cells with VEGF and TNFalpha in ascites from advanced ovarian cancer: association with platinum resistance and prognosis in patients receiving first-line, platinum-based chemotherapy. Gynecol Oncol. 2008;108:421–7.PubMedCrossRef

38.

Santin AD, Bellone S, Ravaggi A, Roman JJ, Pecorelli S, Parham GP, Cannon MJ. Induction of tumour-specific CD8+ cytotoxic T lymphocytes by tumour lysate-pulsed autologous dendritic cells in patients with uterine serous papillary cancer. Br J Cancer. 2002;86:151–7.PubMedPubMedCentralCrossRef

39.

Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348:203–13.PubMedCrossRef

40.

Neves BM, Cruz MT, Francisco V, Garcia-Rodriguez C, Silvestre R, Cordeiro-da-Silva A, Dinis AM, Batista MT, Duarte CB, Lopes MC. Differential roles of PI3-Kinase, MAPKs and NF-kappaB on the manipulation of dendritic cell T(h)1/T(h)2 cytokine/chemokine polarizing profile. Mol Immunol. 2009;46:2481–92.PubMedCrossRef

41.

Leveque L, Deknuydt F, Bioley G, Old LJ, Matsuzaki J, Odunsi K, Ayyoub M, Valmori D. Interleukin 2-mediated conversion of ovarian cancer-associated CD4+ regulatory T cells into proinflammatory interleukin 17-producing helper T cells. J Immunother. 2009;32:101–8.PubMedCrossRef

42.

Liu Q, Muruve DA. Molecular basis of the inflammatory response to adenovirus vectors. Gene Ther. 2003;10:935–40.PubMedCrossRef

43.

Liu Q, White LR, Clark SA, Heffner DJ, Winston BW, Tibbles LA, Muruve DA. Akt/protein kinase B activation by adenovirus vectors contributes to NFkappaB-dependent CXCL10 expression. J Virol. 2005;79:14507–15.PubMedPubMedCentralCrossRef

44.

Ade N, Antonios D, Kerdine-Romer S, Boisleve F, Rousset F, Pallardy M. NF-kappaB plays a major role in the maturation of human dendritic cells induced by NiSO4 but not by DNCB. Toxicol Sci. 2007;99:488–501.PubMedCrossRef

Title: A novel method for efficient generation of antigen-specific effector T-cells using dendritic cells transduced with recombinant adeno-associated virus and p38 kinase blockade
Authors: Leonardo Mirandola
Maurizio Chiriva-Internati
Robert Bresalier
Lucia Piccotti
Fabio Grizzi
Francesco M. Marincola
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Vaccination
Ovarian Cancer
Ovarian Cancer
Published in: Journal of Translational Medicine / Issue 1/2019
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-019-02163-4

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A novel method for efficient generation of antigen-specific effector T-cells using dendritic cells transduced with recombinant adeno-associated virus and p38 kinase blockade

Abstract

Background

Methods

Results

Conclusions

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