Abstract |
Chemotherapy can precondition for immunotherapy by creating an environment for homeostatic lymphoproliferation and eliminating some of the suppressive immune networks. We found that combination therapy with anti-4-1BB and cyclophosphamide (CTX) produced synergistic anticancer effects in the poorly immunogenic B16 melanoma model in mice. The antitumor effect of the combination therapy depended mainly on CD8(+) T cells, the 4-1BB-dependent expansion and differentiation of which into IFN-gamma-producing CD11c(+)CD8(+) T cells was enhanced by CTX. Anti-4-1BB induced a rapid repopulation of T and B cells from CTX-mediated lymphopenia. Anti-4-1BB protected naïve T cells from CTX and promoted proliferation of memory/effector and memory T cells. The combination treatment produced approximately 60- and 2.2-fold more CTLs per tumor-associated antigen compared with CTX or anti-4-1BB alone, respectively. This indicates that anti-4-1BB promoted a preferential expansion of tumor-specific CD8(+) T cells among the repopulated lymphocytes following CTX-mediated lymphopenia. CTX treatment enhanced 4-1BB expression on CD4 and CD8 T cells, and CTX alone or in combination with anti-4-1BB effectively suppressed peripheral regulatory T cells. Our results indicate that anti-4-1BB and CTX can be practical partners in cancer therapy because CTX creates an environment in which anti-4-1BB actively promotes the differentiation and expansion of tumor-specific CTLs.
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Authors | Young H Kim, Beom K Choi, Ho S Oh, Woo J Kang, Robert S Mittler, Byoung S Kwon |
Journal | Molecular cancer therapeutics
(Mol Cancer Ther)
Vol. 8
Issue 2
Pg. 469-78
(Feb 2009)
ISSN: 1535-7163 [Print] United States |
PMID | 19190115
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies, Monoclonal
- Antigens, Neoplasm
- Antineoplastic Agents
- Epitopes
- Forkhead Transcription Factors
- Foxp3 protein, mouse
- Tumor Necrosis Factor Receptor Superfamily, Member 9
- Cyclophosphamide
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Topics |
- Animals
- Antibodies, Monoclonal
(immunology, therapeutic use)
- Antigens, Neoplasm
(immunology)
- Antineoplastic Agents
(pharmacology, therapeutic use)
- Antineoplastic Combined Chemotherapy Protocols
(therapeutic use)
- CD8-Positive T-Lymphocytes
(cytology, drug effects, immunology)
- Cell Proliferation
(drug effects)
- Cyclophosphamide
(pharmacology, therapeutic use)
- Drug Synergism
- Epitopes
- Forkhead Transcription Factors
(metabolism)
- Immunologic Memory
(drug effects)
- Lymphopenia
(drug therapy)
- Melanoma
(drug therapy, immunology)
- Mice
- T-Lymphocytes, Regulatory
(drug effects)
- Tumor Necrosis Factor Receptor Superfamily, Member 9
(antagonists & inhibitors, immunology)
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