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Vaccination using melanoma cells treated with p19arf and interferon beta gene transfer in a mouse model: a novel combination for cancer immunotherapy

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Abstract

Previously, we combined p19Arf (Cdkn2a, tumor suppressor protein) and interferon beta (IFN-β, immunomodulatory cytokine) gene transfer in order to enhance cell death in a murine model of melanoma. Here, we present evidence of the immune response induced when B16 cells succumbing to death due to treatment with p19Arf and IFN-β are applied in vaccine models. Use of dying cells for prophylactic vaccination was investigated, identifying conditions for tumor-free survival. After combined p19Arf and IFN-β treatment, we observed immune rejection at the vaccine site in immune competent and nude mice with normal NK activity, but not in NOD-SCID and dexamethasone immunosuppressed mice (NK deficient). Combined treatment induced IL-15, ULBP1, FAS/APO1 and KILLER/DR5 expression, providing a mechanism for NK activation. Prophylactic vaccination protected against tumor challenge, where markedly delayed progression and leukocyte infiltration were observed. Analysis of primed lymphocytes revealed secretion of TH1-related cytokines and depletion protocols showed that both CD4+ and CD8+ T lymphocytes are necessary for immune protection. However, application of this prophylactic vaccine where cells were treated either with IFN-β alone or combined with p19Arf conferred similar immune protection and cytokine activation, yet only the combination was associated with increased overall survival. In a therapeutic vaccine protocol, only the combination was associated with reduced tumor progression. Our results indicate that by harnessing cell death in an immunogenic context, our p19Arf and IFN-β combination offers a clear advantage when both genes are included in the vaccine and warrants further development as a novel immunotherapy for melanoma.

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Abbreviations

Ad:

Adenovirus

Arf:

Alternate reading frame

CCL:

Chemokine (C–C motif) ligand

CDKN2A:

Cyclin-dependent kinase inhibitor 2A

CXCL:

Chemokine (C–X–C motif) ligand

DEX:

Dexamethasone

EPM-UNIFESP:

Escola Paulista de Medicina-Universidade Federal de São Paulo

FAS/APO1:

Fas receptor/apoptosis antigen 1

FMUSP:

Faculdade de Medicina-Universidade de São Paulo

H60a:

Histocompatibility 60a

ICESP:

Instituto do Câncer do Estado de São Paulo

IU:

Infectious units

KILLER/DR5:

KILLER/death receptor 5

LUC:

Luciferase

MDM2, 4:

Murine double minute 2, 4

MOI:

Multiplicity of infection

NOD-SCID:

Non-obese diabetic-severe combined immunodeficiency

PG:

p53-responsive promoter

PGTxβ:

p53-responsive promoter

Raet 1d, e:

Retinoic acid early transcript 1d, e

RGD:

Argenylglycylaspartic acid

SEM:

Standard error of the mean

TP53:

Tumor protein 53, p53

ULBP1:

UL16-binding protein 1

UNIFESP:

Universidade Federal de São Paulo

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Acknowledgments

We are grateful for the support of the laboratories of Drs. José Eduardo Krieger (Universidade de São Paulo-USP) and Roger Chammas (Universidade de São Paulo-USP). We thank Dr. Elaine Guadelupe Rodrigues (Universidade Federal de São Paulo- UNIFESP) for helpful discussions as well as Jonatan Ersching and Dr. Mauricio Martins Rodrigues (Universidade Federal de São Paulo- UNIFESP) for assistance with antibody production. We also thank Camila Morais Melo (Faculdade de Medicina da Universidade de São Paulo-FMUSP) for assistance in the immunochemistry assay. Sao Paulo Research Foundation grants (Strauss, B.E) 13/25167-5, 11/50911-4; fellowships (Medrano, R.F.V) 13/09474-5, (Ribeiro, A.H) 11/10656-5, (Catani, J.P.P) 14/11524-3.

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Authors and Affiliations

  1. Viral Vector Laboratory, Centro de Investigação Translacional em Oncologia/LIM24, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 251, 8th Floor, São Paulo, SP, 01246-000, Brazil

    Ruan Felipe Vieira Medrano, João Paulo Portela Catani, Aline Hunger Ribeiro & Bryan E. Strauss

  2. Escola Paulista de Medicina-Universidade Federal de São Paulo, São Paulo, Brazil

    Samanta Lopes Tomaz

  3. Animal Care Facility, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

    Christian A. Merkel

  4. Gene Therapy Laboratory, Instituto de Ciências Biomédicas-I, Universidade de São Paulo, São Paulo, Brazil

    Eugenia Costanzi-Strauss

Authors
  1. Ruan Felipe Vieira Medrano
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  2. João Paulo Portela Catani
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  3. Aline Hunger Ribeiro
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  4. Samanta Lopes Tomaz
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  5. Christian A. Merkel
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  6. Eugenia Costanzi-Strauss
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  7. Bryan E. Strauss
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Correspondence to Bryan E. Strauss.

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Medrano, R.F.V., Catani, J.P.P., Ribeiro, A.H. et al. Vaccination using melanoma cells treated with p19arf and interferon beta gene transfer in a mouse model: a novel combination for cancer immunotherapy. Cancer Immunol Immunother 65, 371–382 (2016). https://doi.org/10.1007/s00262-016-1807-8

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  • DOI: https://doi.org/10.1007/s00262-016-1807-8

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