Exploiting a new strategy to induce immunogenic cell death to improve dendritic cell-based vaccines for lymphoma immunotherapy

B. Montico, C. Lapenta, M. Ravo, D. Martorelli, E. Muraro, B. Zeng, E. Comaro, M. Spada, S. Donati, S.M. Santini, R. Tarallo, G. Giurato, F. Rizzo, A. Weisz, F. Belardelli, R. Dolcetti, J. Dal Col

Research output: Contribution to journalArticlepeer-review

Abstract

Although promising, the clinical benefit provided by dendritic cell (DC)-based vaccines is still limited and the choice of the optimal antigen formulation is still an unresolved issue. We have developed a new DC-based vaccination protocol for aggressive and/or refractory lymphomas which combines the unique features of interferon-conditioned DC (IFN-DC) with highly immunogenic tumor cell lysates (TCL) obtained from lymphoma cells undergoing immunogenic cell death. We show that treatment of mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) cell lines with 9-cis-retinoic acid and IFNα (RA/IFNα) induces early membrane exposure of Calreticulin, HSP70 and 90 together with CD47 down-regulation and enhanced HMGB1 secretion. Consistently, RA/IFNα-treated apoptotic cells and -TCLs were more efficiently phagocytosed by DCs compared to controls. Notably, cytotoxic T cells (CTLs) generated with autologous DCs pulsed with RA/IFNα-TCLs more efficiently recognized and specifically lysed MCL or DLBCL cells or targets loaded with several HLA-A*0201 cyclin D1 or HLA-B*0801 survivin epitopes. These cultures also showed an expansion of Th1 and Th17 cells and an increased Th17/Treg ratio. Moreover, DCs loaded with RA/IFNα-TCLs showed enhanced functional maturation and activation. NOD/SCID mice reconstituted with human peripheral blood lymphocytes and vaccinated with autologous RA/IFNα-TCL loaded-IFN-DCs showed lymphoma-specific T-cell responses and a significant decrease in tumor growth with respect to mice treated with IFN-DC unpulsed or loaded with untreated TCLs. This study demonstrates the feasibility and efficacy of the use of RA/IFNα to generate a highly immunogenic TCL as a suitable tumor antigen formulation for the development of effective anticancer DC-based vaccines. © 2017 Taylor & Francis Group, LLC.
Original languageEnglish
JournalOncoImmunology
Volume6
Issue number11
DOIs
Publication statusPublished - 2017

Keywords

  • alitretinoin
  • alpha interferon
  • calreticulin
  • CD47 antigen
  • dendritic cell vaccine
  • heat shock protein 70
  • heat shock protein 90
  • high mobility group B1 protein
  • immunoglobulin enhancer binding protein
  • major histocompatibility antigen class 2
  • survivin
  • synthetic peptide
  • toll like receptor
  • tumor antigen
  • animal cell
  • animal experiment
  • animal model
  • apoptosis
  • Article
  • cell activation
  • cell death
  • cell maturation
  • cell specificity
  • cytotoxic T lymphocyte
  • diffuse large B cell lymphoma
  • down regulation
  • flow cytometry
  • gene expression
  • gene ontology
  • immunophenotyping
  • immunotherapy
  • lymphoma cell
  • mantle cell lymphoma
  • mouse
  • nonhuman
  • peripheral lymphocyte
  • regulatory T lymphocyte
  • RNA purification
  • RNA sequence
  • Th1 cell
  • Th17 cell
  • tumor cell
  • tumor cell destruction
  • Western blotting

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