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Blockade of CTLA-4 promotes the development of effector CD8+ T lymphocytes and the therapeutic effect of vaccination with an attenuated protozoan expressing NY-ESO-1

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Abstract

The development of cancer immunotherapy has long been a challenge. Here, we report that prophylactic vaccination with a highly attenuated Trypanosoma cruzi strain expressing NY-ESO-1 (CL-14-NY-ESO-1) induces both effector memory and effector CD8+ T lymphocytes that efficiently prevent tumor development. However, the therapeutic effect of such a vaccine is limited. We also demonstrate that blockade of Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) during vaccination enhances the frequency of NY-ESO-1-specific effector CD8+ T cells producing IFN-γ and promotes lymphocyte migration to the tumor infiltrate. As a result, therapy with CL-14-NY-ESO-1 together with anti-CTLA-4 is highly effective in controlling the development of an established melanoma.

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Abbreviations

ACK:

Ammonium Chloride Potassium

CD8+TCM :

Central Memory CD8+ T cells

CD8+TE :

Effector CD8+ T cells

CD8+TEM :

Effector Memory CD8+ T cells

CTA:

Cancer Testis Antigens

CTLA-4:

Cytotoxic T Lymphocyte Antigen 4

FBS:

Fetal Bovine Serum

gzmB:

Granzyme B

HBSS:

Hank’s Balanced Salt Solution

HEPES:

4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

i.p.:

Intraperitoneal injection

IFN:

Interferon

IL:

Interleukin

MHC:

Major Histocompatibility Complex

PBS:

Phosphate-buffered saline

TI:

Tumor Infiltrate

Tregs:

Regulatory T cells

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Acknowledgments

We thank the Ludwig Institute of Cancer Research (LICR) Tetramer Facility for tetramer synthesis; the LICR–Cornell University for the recombinant NY-ESO-1 protein; Dr. James Allison from the Memorial Sloan-Kettering Cancer Center for providing the anti-CTLA-4 monoclonal antibody (9D9 hybridoma); Dr. Jonathan Cebon from LICR–Melbourne for providing the B16-NY-ESO-1 cell lines; Dr. Luiz Travassos from São Paulo University and Dr. Kevin Maloy from University of Oxford for incentive, scientific discussions, and suggestions during the development of this work. Grant support: Atlantic Philanthropies/Program of Clinical Discoveries from the LICR, Fundação de Amparo a Pesquisa de Minas Gerais, Fundação Oswaldo Cruz, and the National Institute of Science and Technology for Vaccines/Conselho Nacional de Desenvolvimento Científico e Tecnológico.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, 30190-002, Brazil

    Luara Isabela dos Santos, Bruno Galvão-Filho, Paula Cristina de Faria, Caroline Junqueira, Miriam Santos Dutra, Lis Ribeiro Antonelli & Ricardo Tostes Gazzinelli

  2. Departamento de Bioquimica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil

    Luara Isabela dos Santos, Bruno Galvão-Filho, Caroline Junqueira, Miriam Santos Dutra, Santuza Maria Ribeiro Teixeira & Ricardo Tostes Gazzinelli

  3. Centro de Terapia Celular e Molecular, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, 04044-010, Brazil

    Maurício Martins Rodrigues

  4. New York Branch at Memorial Sloan-Kettering Cancer Center, Ludwig Institute for Cancer Research, New York, NY, 10065-6007, USA

    Gerd Ritter

  5. Department of Microbiology and Immunology, Howard Hughes Medical Institute, University of California, San Francisco, CA, USA

    Oliver Bannard

  6. Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, CB2 2QH, UK

    Douglas Thomas Fearon

  7. Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA, 01605-02324, USA

    Ricardo Tostes Gazzinelli

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  1. Luara Isabela dos Santos
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Correspondence to Ricardo Tostes Gazzinelli.

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dos Santos, L.I., Galvão-Filho, B., de Faria, P.C. et al. Blockade of CTLA-4 promotes the development of effector CD8+ T lymphocytes and the therapeutic effect of vaccination with an attenuated protozoan expressing NY-ESO-1. Cancer Immunol Immunother 64, 311–323 (2015). https://doi.org/10.1007/s00262-014-1634-8

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