Breaking immune tolerance by targeting CD25+ regulatory T cells is essential for the anti-tumor effect of the CTLA-4 blockade in an HLA-DR transgenic mouse model of prostate cancer.
Prostate
; 74(14): 1423-32, 2014 Oct.
Article
en En
| MEDLINE
| ID: mdl-25111463
ABSTRACT
INTRODUCTION:
Recent studies suggest that the cancer immunotherapy based on the blockade of the CTLA-4-mediated inhibitory pathway is efficacious only in select populations, predominantly for immunogenic tumors or when delivered in combination with modalities that can break immunologic tolerance to tumor antigens.METHODS:
We studied the effect of CD25+ cell depletion and CTLA-4 blockade on the growth of Transgenic Mouse Adenocarcinoma of Prostate (TRAMP)-PSA tumor cells in DR2bxPSA F1 mice. In these mice, immunological tolerance to PSA was established in a context of the HLA-DRB1*1501(DR2b) allele.RESULTS:
In our model, single administration of anti-CD25 antibody prior to tumor inoculation significantly increased IFN-γ production in response to the CD8 T cell epitope PSA65-73 , and delayed TRAMP-PSA tumor growth compared to mice treated with isotype control antibodies. In contrast, the anti-tumor effect of the anti-CTLA-4 antibody as a monotherapy was marginal. The combinatory treatment with anti-CD25/anti-CTLA-4 antibodies significantly enhanced anti-tumor immunity and caused more profound delay in tumor growth compared to each treatment alone. The proportion of tumor-free animals was higher in the group that received combination treatment (21%) compared to other groups (2-7%). The enhanced anti-tumor immunity in response to the CD25 depletion or CTLA-4 blockade was only seen in the immunogenic TRAMP-PSA tumor model, whereas the effect was completely absent in mice bearing poorly immunogenic TRAMP-C1 tumors.DISCUSSION:
Our data suggest that breaking immunological tolerance to "self" antigens is essential for the therapeutic effect of CTLA-4 blockade. Such combinatory treatment may be a promising approach for prostate cancer immunotherapy.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias de la Próstata
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Linfocitos T Reguladores
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Subunidad alfa del Receptor de Interleucina-2
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Antígeno CTLA-4
Tipo de estudio:
Clinical_trials
Límite:
Animals
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Humans
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Male
Idioma:
En
Año:
2014
Tipo del documento:
Article