Phage-Based Anti-HER2 Vaccination Can Circumvent Immune Tolerance against Breast Cancer

Cancer Immunology Research - Tập 6 Số 12 - Trang 1486-1498 - 2018
Caterina Bartolacci1, Cristina Andreani1, Claudia Curcio2,3, Sergio Occhipinti3, Luca Massaccesi4, Mirella Giovarelli3, Roberta Galeazzi4, Manuela Iezzi2, Martina Tilio1, Valentina Gambini1, Junbiao Wang1, Cristina Marchini1, Augusto Amici1
11Department of Biosciences and Veterinary Medicine University of Camerino, Camerino, Italy.
22Aging Research Centre, G. d'Annunzio University, Chieti, Italy.
33Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies, University of Torino, Torino, Italy.
44Dipartimento di Scienze della Vita e dell'Ambiente, Università Politecnica delle Marche, Ancona, Italy.

Tóm tắt

Abstract Δ16HER2 is a splice variant of HER2 and defined as the transforming isoform in HER2-positive breast cancer. It has been shown that Δ16HER2 promotes breast cancer aggressiveness and drug resistance. In the present work, we used in silico modeling to identify structural differences between Δ16HER2 and the wild-type HER2 proteins. We then developed DNA vaccines specifically against the Δ16HER2 isoform and showed that these immunotherapies hampered carcinogenesis in a breast cancer transplantable model. However, the vaccines failed to elicit immune protection in Δ16HER2 transgenic mice because of tolerogenic mechanisms toward the human HER2 self-antigen, a scenario commonly seen in HER2+ patients. Thus, we engineered bacteriophages with immunogenic epitopes of Δ16HER2 exposed on their coat for use as anticancer vaccines. These phage-based vaccines were able to break immune tolerance, triggering a protective anti-Δ16HER2 humoral response. These findings provide a rationale for the use of phage-based anti-HER2/Δ16HER2 vaccination as a safe and efficacious immunotherapy against HER2-positive breast cancers.

Từ khóa


Tài liệu tham khảo

Sorlie, 2003, Repeated observation of breast tumor subtypes in independent gene expression data sets, Proc Natl Acad Sci USA, 100, 8418, 10.1073/pnas.0932692100

Yamauchi, 2001, The role of c-erbB-2 as a predictive factor in breast cancer, Breast Cancer, 8, 171, 10.1007/BF02967506

Siegel, 2012, Cancer treatment and survivorship statistics, 2012, CA Cancer J Clin, 62, 220, 10.3322/caac.21149

Mendes, 2015, The benefit of HER2-targeted therapies on overall survival of patients with metastatic HER2-positive breast cancer–a systematic review, Breast Cancer Res, 17, 140, 10.1186/s13058-015-0648-2

Rexer, 2012, Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications, Crit Rev Oncog, 17, 1, 10.1615/CritRevOncog.v17.i1.20

Finn, 2018, The dawn of vaccines for cancer prevention, Nat Rev Immunol, 18, 183, 10.1038/nri.2017.140

Mittendorf, 2016, Injecting hope–a review of breast cancer vaccines, Oncology, 30, 475

Moasser, 2007, The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis, Oncogene, 26, 6469, 10.1038/sj.onc.1210477

Castiglioni, 2006, Role of exon-16-deleted HER2 in breast carcinomas, Endocr Relat Cancer, 13, 221, 10.1677/erc.1.01047

Mitra, 2009, An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance, Mol Cancer Ther, 8, 2152, 10.1158/1535-7163.MCT-09-0295

Alajati, 2013, Mammary tumor formation and metastasis evoked by a HER2 splice variant, Cancer Res, 73, 5320, 10.1158/0008-5472.CAN-12-3186

Ursini-Siegel, 2007, Insights from transgenic mouse models of ERBB2-induced breast cancer, Nat Rev Cancer, 7, 389, 10.1038/nrc2127

Siegel, 1999, Elevated expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer, EMBO J, 18, 2149, 10.1093/emboj/18.8.2149

Kwong, 1998, A novel splice variant of HER2 with increased transformation activity, Mol Carcinog, 23, 62, 10.1002/(SICI)1098-2744(199810)23:2<62::AID-MC2>3.0.CO;2-O

Huynh, 2014, MicroRNA-7 inhibits multiple oncogenic pathways to suppress HER2Delta16 mediated breast tumorigenesis and reverse trastuzumab resistance, PLoS One, 9, e114419, 10.1371/journal.pone.0114419

Tilio, 2016, Irreversible inhibition of Delta16HER2 is necessary to suppress Delta16HER2-positive breast carcinomas resistant to lapatinib, Cancer Lett, 381, 76, 10.1016/j.canlet.2016.07.028

Gabrielli, 2013, Identification of relevant conformational epitopes on the HER2 oncoprotein by using Large Fragment Phage Display (LFPD), PLoS One, 8, e58358, 10.1371/journal.pone.0058358

Marchini, 2011, The human splice variant Delta16HER2 induces rapid tumor onset in a reporter transgenic mouse, PLoS One, 6, e18727, 10.1371/journal.pone.0018727

Andreani, 2017, Resveratrol fuels HER2 and ERalpha-positive breast cancer behaving as proteasome inhibitor, Aging, 9, 508, 10.18632/aging.101175

Bostrom, 2009, Variants of the antibody herceptin that interact with HER2 and VEGF at the antigen binding site, Science, 323, 1610, 10.1126/science.1165480

Fisher, 2010, Structure of the complex between HER2 and an antibody paratope formed by side chains from tryptophan and serine, J Mol Biol, 402, 217, 10.1016/j.jmb.2010.07.027

Bocharov, 2008, Spatial structure of the dimeric transmembrane domain of the growth factor receptor ErbB2 presumably corresponding to the receptor active state, J Biol Chem, 283, 6950, 10.1074/jbc.M709202200

Red Brewer, 2009, The juxtamembrane region of the EGF receptor functions as an activation domain, Mol Cell, 34, 641, 10.1016/j.molcel.2009.04.034

Aertgeerts, 2011, Structural analysis of the mechanism of inhibition and allosteric activation of the kinase domain of HER2 protein, J Biol Chem, 286, 18756, 10.1074/jbc.M110.206193

Uchida, 2000, Epidermal sphingomyelins are precursors for selected stratum corneum ceramides, J Lipid Res, 41, 2071, 10.1016/S0022-2275(20)32369-5

Galeazzi, 2014, Insights into the influence of 5-HT2c aminoacidic variants with the inhibitory action of serotonin inverse agonists and antagonists, J Mol Model, 20, 2120, 10.1007/s00894-014-2120-0

Fiser, 2003, ModLoop: automated modeling of loops in protein structures, Bioinformatics, 19, 2500, 10.1093/bioinformatics/btg362

Ko, 2012, GalaxyWEB server for protein structure prediction and refinement, Nucleic Acids Res, 40, W294, 10.1093/nar/gks493

Biasini, 2014, SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information, Nucleic Acids Res, W252, 10.1093/nar/gku340

Ceroni, 2006, DISULFIND: a disulfide bonding state and cysteine connectivity prediction server, Nucleic Acids Res, 34, W177, 10.1093/nar/gkl266

Jo, 2008, CHARMM-GUI: a web-based graphical user interface for CHARMM, J Comput Chem, 29, 1859, 10.1002/jcc.20945

Disis, 1998, Human HER-2/neu protein immunization circumvents tolerance to rat neu: a vaccine strategy for ‘self’ tumour antigens, Immunology, 93, 192, 10.1046/j.1365-2567.1998.00424.x

Quaglino, 2010, A better immune reaction to Erbb-2 tumors is elicited in mice by DNA vaccines encoding rat/human chimeric proteins, Cancer Res, 70, 2604, 10.1158/0008-5472.CAN-09-2548

Reverberi, 2007, Factors affecting the antigen-antibody reaction, Blood Transfus, 5, 227

Watson, 2003, Molecular biology of the gene

Rolla, 2008, Protective immunity against neu-positive carcinomas elicited by electroporation of plasmids encoding decreasing fragments of rat neu extracellular domain, Hum Gene Ther, 19, 229, 10.1089/hum.2006.196

Betts, 2003, Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation, J Immunol Methods, 281, 65, 10.1016/S0022-1759(03)00265-5

Hori, 2003, Control of regulatory T cell development by the transcription factor Foxp3, Science, 299, 1057, 10.1126/science.1079490

Allard, 2016, CD73-adenosine: a next-generation target in immuno-oncology, Immunotherapy, 8, 145, 10.2217/imt.15.106

Wu, 2002, Phage display particles expressing tumor-specific antigens induce preventive and therapeutic anti-tumor immunity in murine p815 model, Int J Cancer, 98, 748, 10.1002/ijc.10260

Fang, 2005, The potential of phage display virions expressing malignant tumor specific antigen MAGE-A1 epitope in murine model, Vaccine, 23, 4860, 10.1016/j.vaccine.2005.05.024

Hodyra-Stefaniak, 2015, Mammalian Host-Versus-Phage immune response determines phage fate in vivo, Sci Rep, 5, 14802, 10.1038/srep14802

Liu, 2005, Human clinical trials of plasmid DNA vaccines, Adv Genet, 55, 25, 10.1016/S0065-2660(05)55002-8

Marchini, 2013, Tailoring DNA vaccines: designing strategies against HER2-positive cancers, Front Oncol, 3, 122, 10.3389/fonc.2013.00122

Lollini, 2003, Cancer immunoprevention: tracking down persistent tumor antigens, Trends Immunol, 24, 62, 10.1016/S1471-4906(02)00030-3

Occhipinti, 2014, Chimeric rat/human HER2 efficiently circumvents HER2 tolerance in cancer patients, Clin Cancer Res, 20, 2910, 10.1158/1078-0432.CCR-13-2663

Quaglino, 2008, ErbB2 transgenic mice: a tool for investigation of the immune prevention and treatment of mammary carcinomas, Curr Protoc Immunol, 10.1002/0471142735.im2009s82

Chen, 1998, DNA vaccines encoding full-length or truncated Neu induce protective immunity against Neu-expressing mammary tumors, Cancer Res, 58, 1965

Quaglino, 2004, Electroporated DNA vaccine clears away multifocal mammary carcinomas in her-2/neu transgenic mice, Cancer Res, 64, 2858, 10.1158/0008-5472.CAN-03-2962

Cho, 2003, Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab, Nature, 421, 756, 10.1038/nature01392

Reilly, 2000, HER-2/neu is a tumor rejection target in tolerized HER-2/neu transgenic mice, Cancer Res, 60, 3569

Anderson, 2002, Projection of an immunological self shadow within the thymus by the aire protein, Science, 298, 1395, 10.1126/science.1075958

Jin, 2010, CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression, Cancer Res, 70, 2245, 10.1158/0008-5472.CAN-09-3109

Meynell, 1968, Filamentous Phages specific for the I Sex Factor, Nature, 217, 1184, 10.1038/2171184a0

Gao, 2010, Phage display and its application in vaccine design, Ann Microbiol, 60, 13, 10.1007/s13213-009-0014-7

Sartorius, 2008, The use of filamentous bacteriophage fd to deliver MAGE-A10 or MAGE-A3 HLA-A2-restricted peptides and to induce strong antitumor CTL responses, J Immunol, 180, 3719, 10.4049/jimmunol.180.6.3719

Grabowska, 2000, Immunisation with phage displaying peptides representing single epitopes of the glycoprotein G can give rise to partial protective immunity to HSV-2, Virology, 269, 47, 10.1006/viro.2000.0185

Roehnisch, 2014, Phage idiotype vaccination: first phase I/II clinical trial in patients with multiple myeloma, J Transl Med, 12, 119, 10.1186/1479-5876-12-119

Jacob, 2010, Combining human and rat sequences in her-2 DNA vaccines blunts immune tolerance and drives antitumor immunity, Cancer Res, 70, 119, 10.1158/0008-5472.CAN-09-2554

Thông tin
Thông tin xuất bản

Cancer Immunology Research

Tập 6 Số 12

1486-1498

Thông tin tác giả