Back to Search
Start Over
CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2006 Jul; Vol. 116 (7), pp. 1935-45. Date of Electronic Publication: 2006 Jun 15. - Publication Year :
- 2006
-
Abstract
- CTL-associated antigen 4 (CTLA4) blockade releases inhibitory controls on T cell activation and proliferation, inducing antitumor immunity in both preclinical and early clinical trials. We examined the mechanisms of action of anti-CTLA4 and a GM-CSF-transduced tumor cell vaccine (Gvax) and their impact on the balance of effector T cells (Teffs) and Tregs in an in vivo model of B16/BL6 melanoma. Tumor challenge increased the frequency of Tregs in lymph nodes, and untreated tumors became infiltrated by CD4+Foxp3- and CD4+Foxp3+ T cells but few CD8+ T cells. Anti-CTLA4 did not deplete Tregs or permanently impair their function but acted in a cell-intrinsic manner on both Tregs and Teffs, allowing them to expand, most likely in response to self antigen. While Gvax primed the tumor-reactive Teff compartment, inducing activation, tumor infiltration, and a delay in tumor growth, the combination with CTLA4 blockade induced greater infiltration and a striking change in the intratumor balance of Tregs and Teffs that directly correlated with tumor rejection. The data suggest that Tregs control both CD4+ and CD8+ T cell activity within the tumor, highlight the importance of the intratumor ratio of effectors to regulators, and demonstrate inversion of the ratio and correlation with tumor rejection during Gvax/anti-CTLA4 immunotherapy.
- Subjects :
- Animals
Antigens, CD
CD4 Antigens immunology
CD8 Antigens immunology
CTLA-4 Antigen
Cancer Vaccines immunology
Cancer Vaccines therapeutic use
Cell Line, Tumor
Cell Proliferation
Forkhead Transcription Factors immunology
Lymph Nodes cytology
Mice
Mice, Inbred C57BL
Antigens, Differentiation immunology
Antigens, Differentiation therapeutic use
Granulocyte-Macrophage Colony-Stimulating Factor immunology
Granulocyte-Macrophage Colony-Stimulating Factor therapeutic use
Immunotherapy
Melanoma, Experimental immunology
Melanoma, Experimental therapy
T-Lymphocyte Subsets immunology
T-Lymphocytes, Regulatory immunology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9738
- Volume :
- 116
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 16778987
- Full Text :
- https://doi.org/10.1172/JCI27745