High-dose cyclophosphamide-mediated anti-tumor effects by the superior expansion of CD44(high) cells after their selective depletion.
As alkylating agents, cyclophosphamides (CTX) are used to treat various cancers and, ironically, to boost immune responses. In the present study, we attempted to elucidate the mechanism responsible for the immunomodulatory effect of high-dose CTX in an established tumor model. A single injection of high-dose CTX increased the survival rate of immunocompetent, but not immunodeficient, mice. Notably, 10 days after CTX injection, the number of CD44(high) memory T cells significantly increased, without a selective decrease in the actual number and percentage of CD4+CD25+Foxp3+ regulatory T cells (Tregs). However, the proportion of Tregs among CD4+ T cells decreased due to expansion of memory and other CD4+ T cell subtypes. This outcome was accompanied by an increase in IL-15 mRNA and up-regulation of IL-15 receptors in the CD44+CD8+ T cell compartment. We postulate that the CTX-induced change in T cell balance may increase anti-tumor immunity.
Hong
So-Hee
SH
Department of Microbiology and Immunology, Seoul National University College of Medicine, 28 Yongon-dong Chongno-gu, Seoul 110-799, South Korea.
Yoon
Il-Hee
IH
Kim
Yong-Hee
YH
Yang
Seung-Ha
SH
Park
Min-Jung
MJ
Nam
Hye-Young
HY
Kim
Bongi
B
Kim
Youngji
Y
Park
Chan-Sik
CS
Park
Chung-Gyu
CG
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002469:Cell Separation; D003520:Cyclophosphamide / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000276:immunology*; D007156:Immunologic Memory / Q000187:drug effects*; D019409:Interleukin-15 / Q000096:biosynthesis / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger; D053647:Receptors, Interleukin-15 / Q000096:biosynthesis / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation
D000970:Antineoplastic Agents; D018960:Hyaluronan Receptors; D019409:Interleukin-15; D012333:RNA, Messenger; D053647:Receptors, Interleukin-15; D003520:Cyclophosphamide