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

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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.

Original languageEnglish
Article numbere1356964
JournalOncoImmunology
Volume6
Issue number11
DOIs
Publication statusPublished - Nov 2 2017

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Immunotherapy
Dendritic Cells
Tretinoin
Lymphoma
Cell Death
Vaccines
Mantle-Cell Lymphoma
Lymphoma, Large B-Cell, Diffuse
Interferons
Neoplasms
Calreticulin
HMGB1 Protein
Th17 Cells
Inbred NOD Mouse
Th1 Cells
HLA-B Antigens
SCID Mice
T-Cell Lymphoma
Cyclin D1
Feasibility Studies

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

Cite this

Exploiting a new strategy to induce immunogenic cell death to improve dendritic cell-based vaccines for lymphoma immunotherapy. / Montico, B.; Lapenta, C.; Ravo, M.; Martorelli, D.; Muraro, E.; Zeng, B.; Comaro, E.; Spada, M.; Donati, S.; Santini, S. M.; Tarallo, R.; Giurato, G.; Rizzo, F.; Weisz, A.; Belardelli, F.; Dolcetti, R.; Dal Col, J.

In: OncoImmunology, Vol. 6, No. 11, e1356964, 02.11.2017.

Research output: Contribution to journalArticle

Montico, B, Lapenta, C, Ravo, M, Martorelli, D, Muraro, E, Zeng, B, Comaro, E, Spada, M, Donati, S, Santini, SM, Tarallo, R, Giurato, G, Rizzo, F, Weisz, A, Belardelli, F, Dolcetti, R & Dal Col, J 2017, 'Exploiting a new strategy to induce immunogenic cell death to improve dendritic cell-based vaccines for lymphoma immunotherapy', OncoImmunology, vol. 6, no. 11, e1356964. https://doi.org/10.1080/2162402X.2017.1356964
Montico, B. ; Lapenta, C. ; Ravo, M. ; Martorelli, D. ; Muraro, E. ; Zeng, B. ; Comaro, E. ; Spada, M. ; Donati, S. ; Santini, S. M. ; Tarallo, R. ; Giurato, G. ; Rizzo, F. ; Weisz, A. ; Belardelli, F. ; Dolcetti, R. ; Dal Col, J. / Exploiting a new strategy to induce immunogenic cell death to improve dendritic cell-based vaccines for lymphoma immunotherapy. In: OncoImmunology. 2017 ; Vol. 6, No. 11.
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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.",
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AU - Montico, B.

AU - Lapenta, C.

AU - Ravo, M.

AU - Martorelli, D.

AU - Muraro, E.

AU - Zeng, B.

AU - Comaro, E.

AU - Spada, M.

AU - Donati, S.

AU - Santini, S. M.

AU - Tarallo, R.

AU - Giurato, G.

AU - Rizzo, F.

AU - Weisz, A.

AU - Belardelli, F.

AU - Dolcetti, R.

AU - Dal Col, J.

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