In pancreatic cancer, chemotherapy increases antitumor responses to tumor-associated antigens and potentiates DNA vaccination
Background Pancreatic ductal adenocarcinoma (PDA) is an almost incurable tumor that is mostly resistant to chemotherapy (CT). Adaptive immune responses to tumor-associated antigens (TAA) have been reported, but immunotherapy (IT) clinical trials have not yet achieved any significant increase in surv...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e001071.full |
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| author | Paola Cappello Francesco Novelli Giorgia Mandili Claudia Curcio Sara Bulfamante Laura Follia Giulio Ferrero Emanuela Mazza Moitza Principe Francesca Cordero Maria Antonietta Satolli Rosella Spadi Andrea Evangelista Daniele Giordano Duy Viet |
| author_facet | Paola Cappello Francesco Novelli Giorgia Mandili Claudia Curcio Sara Bulfamante Laura Follia Giulio Ferrero Emanuela Mazza Moitza Principe Francesca Cordero Maria Antonietta Satolli Rosella Spadi Andrea Evangelista Daniele Giordano Duy Viet |
| author_sort | Paola Cappello |
| collection | DOAJ |
| description | Background Pancreatic ductal adenocarcinoma (PDA) is an almost incurable tumor that is mostly resistant to chemotherapy (CT). Adaptive immune responses to tumor-associated antigens (TAA) have been reported, but immunotherapy (IT) clinical trials have not yet achieved any significant increase in survival, confirming the suppressive environment of PDA. As CT has immune-modulating properties, we investigated the effect of gemcitabine (GEM) in antitumor effector responses to TAA in patients with PDA.Methods The IgG antibody repertoire in patients with PDA before and after CT was profiled by serological proteome analysis and ELISA and their ability to activate complement-dependent cytotoxicity (CDC) was measured. Peripheral T cells were stimulated in vitro with recombinant TAA, and specific proliferation, IFN-γ/IL-10 and CD8+/Treg ratios were measured. Mice that spontaneously developed PDA were treated with GEM and inoculated with an ENO1 (α−Enolase) DNA vaccine. In some experimental groups, the effect of depleting CD4, CD8 and B cells by specific antibodies was also evaluated.Results CT increased the number of TAA recognized by IgG and their ability to activate CDC. Evaluation of the IFN-γ/IL-10 ratio and CD8+/Treg ratios revealed that CT treatment shifted T cell responses to ENO1, G3P (glyceraldheyde-3-phosphate dehydrogenase), K2C8 (keratin, type II cytoskeletal 8) and FUBP1 (far upstream binding protein 1), four of the most recognized TAA, from regulatory to effector. In PDA mice models, treatment with GEM prior to ENO1 DNA vaccination unleashed CD4 antitumor activity and strongly impaired tumor progression compared with mice that were vaccinated or GEM-treated alone.Conclusions Overall, these data indicate that, in PDA, CT enhances immune responses to TAA and renders them suitable targets for IT. |
| format | Article |
| id | doaj-art-f1f39e8305ee4d40b27f560edc1298f6 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-f1f39e8305ee4d40b27f560edc1298f62024-11-09T22:50:16ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-001071In pancreatic cancer, chemotherapy increases antitumor responses to tumor-associated antigens and potentiates DNA vaccinationPaola Cappello0Francesco Novelli1Giorgia Mandili2Claudia Curcio3Sara Bulfamante4Laura Follia5Giulio Ferrero6Emanuela Mazza7Moitza Principe8Francesca Cordero9Maria Antonietta Satolli10Rosella Spadi11Andrea Evangelista12Daniele Giordano13Duy Viet141 Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy1 Department of Molecular Biotechnology and Health Sciences, University of Turin, Torino, Italy1 Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy1 Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy1 Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy1 Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy3 Computer Science Department, University of Turin, Turin, Italy1 Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy1 Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy3 Computer Science Department, University of Turin, Turin, Italy4 Department of Surgical Sciences, University of Turin, Torino, Italy5 Centro Oncologico Ematologico Subalpino, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy6 Servizio di Epidemiologia Clinica, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy1 Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy1 Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, ItalyBackground Pancreatic ductal adenocarcinoma (PDA) is an almost incurable tumor that is mostly resistant to chemotherapy (CT). Adaptive immune responses to tumor-associated antigens (TAA) have been reported, but immunotherapy (IT) clinical trials have not yet achieved any significant increase in survival, confirming the suppressive environment of PDA. As CT has immune-modulating properties, we investigated the effect of gemcitabine (GEM) in antitumor effector responses to TAA in patients with PDA.Methods The IgG antibody repertoire in patients with PDA before and after CT was profiled by serological proteome analysis and ELISA and their ability to activate complement-dependent cytotoxicity (CDC) was measured. Peripheral T cells were stimulated in vitro with recombinant TAA, and specific proliferation, IFN-γ/IL-10 and CD8+/Treg ratios were measured. Mice that spontaneously developed PDA were treated with GEM and inoculated with an ENO1 (α−Enolase) DNA vaccine. In some experimental groups, the effect of depleting CD4, CD8 and B cells by specific antibodies was also evaluated.Results CT increased the number of TAA recognized by IgG and their ability to activate CDC. Evaluation of the IFN-γ/IL-10 ratio and CD8+/Treg ratios revealed that CT treatment shifted T cell responses to ENO1, G3P (glyceraldheyde-3-phosphate dehydrogenase), K2C8 (keratin, type II cytoskeletal 8) and FUBP1 (far upstream binding protein 1), four of the most recognized TAA, from regulatory to effector. In PDA mice models, treatment with GEM prior to ENO1 DNA vaccination unleashed CD4 antitumor activity and strongly impaired tumor progression compared with mice that were vaccinated or GEM-treated alone.Conclusions Overall, these data indicate that, in PDA, CT enhances immune responses to TAA and renders them suitable targets for IT.https://jitc.bmj.com/content/8/2/e001071.full |
| spellingShingle | Paola Cappello Francesco Novelli Giorgia Mandili Claudia Curcio Sara Bulfamante Laura Follia Giulio Ferrero Emanuela Mazza Moitza Principe Francesca Cordero Maria Antonietta Satolli Rosella Spadi Andrea Evangelista Daniele Giordano Duy Viet In pancreatic cancer, chemotherapy increases antitumor responses to tumor-associated antigens and potentiates DNA vaccination Journal for ImmunoTherapy of Cancer |
| title | In pancreatic cancer, chemotherapy increases antitumor responses to tumor-associated antigens and potentiates DNA vaccination |
| title_full | In pancreatic cancer, chemotherapy increases antitumor responses to tumor-associated antigens and potentiates DNA vaccination |
| title_fullStr | In pancreatic cancer, chemotherapy increases antitumor responses to tumor-associated antigens and potentiates DNA vaccination |
| title_full_unstemmed | In pancreatic cancer, chemotherapy increases antitumor responses to tumor-associated antigens and potentiates DNA vaccination |
| title_short | In pancreatic cancer, chemotherapy increases antitumor responses to tumor-associated antigens and potentiates DNA vaccination |
| title_sort | in pancreatic cancer chemotherapy increases antitumor responses to tumor associated antigens and potentiates dna vaccination |
| url | https://jitc.bmj.com/content/8/2/e001071.full |
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