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Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2008 Sep 01; Vol. 205 (9), pp. 2125-38. Date of Electronic Publication: 2008 Aug 25. - Publication Year :
- 2008
-
Abstract
- Interference with inhibitory immunological checkpoints controlling T cell activation provides new opportunities to augment cancer immunotherapies. Whereas cytotoxic T lymphocyte-associated antigen-4 blockade has shown promising preclinical and clinical results, therapeutic CD4(+)CD25(+) T reg cell depletion has failed to consistently enhance immune-based therapies. Using B16/BL6, a transplantable murine melanoma model, we show a dichotomy between the effects of T reg cell depletion on tumor rejection dependent on whether depletion occurs before (prophylactic) or after (therapeutic) tumor engraftment. Failure to promote rejection with therapeutic depletion is not related to lack of T reg cell depletion, to elimination of CD25(+) effector T cells, or to a failure to enhance systemic antitumor T cell responses, but correlates with failure of effector cells to infiltrate the tumor and increase the intratumor ratio of effector T cell/T reg cell. Finally, systemic antitumor responses generated upon therapeutic T reg cell depletion are significantly stronger than those generated in the presence of T reg cells, and are capable of eliciting rejection of established tumors after transfer into immunoablated recipients receiving combination immunotherapy. The data demonstrate a dissociation between measurable systemic responses and tumor rejection during CD25-directed T reg cell depletion, and suggest an alternative, clinically applicable strategy for the treatment of established tumors.
- Subjects :
- Animals
CD4-Positive T-Lymphocytes metabolism
Cancer Vaccines immunology
Immune System
Interleukin-2 Receptor alpha Subunit biosynthesis
Lymphocyte Depletion
Melanoma, Experimental
Mice
Mice, Inbred C57BL
Mice, Transgenic
Models, Biological
Phenotype
T-Lymphocytes metabolism
Immunotherapy methods
Neoplasms immunology
Neoplasms metabolism
T-Lymphocytes cytology
Subjects
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 205
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 18725522
- Full Text :
- https://doi.org/10.1084/jem.20080099