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.
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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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DOI: https://doi.org/10.1007/s00262-014-1634-8