Journal
MOLECULAR CANCER THERAPEUTICS
Volume 8, Issue 2, Pages 469-478Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-08-0993
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Funding
- NIH National Eye Institute [R01EY013325]
- National Cancer Center, Korea [NCC-0810720-1, NCCF-0890301-1]
- Korean Science and Engineering Foundation [M10641000040, M10870060009]
- Korea Health 21 RD [A050260]
- Arthritis Foundation, Atlanta, GA
- Korea Research Foundation [KRF-2005-201-E00008, KRF-2005-084-E00001]
- National Research Foundation of Korea [2005-201-E00008] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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 naive T cells from CTX and promoted proliferation of memory/effector and memory T cells. The combination treatment produced similar to 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. [Mol Cancer Ther 2009;8(2):469-78]
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