Doxorubicin enhances CD4(+) T-cell immune responses by inducing expression of CD40 ligand and 4-1BB.
Chemotherapy agents have adverse immunotherapeutic effects secondary to inhibition of hematopoietic stem cell proliferation, particularly in committed lymphoblast. Certain anti-cancer drugs have immuno-modulatory properties, although mechanisms are still not fully understood. In the current study, we explored the effects of doxorubicin on peripheral blood CD4(+) and CD8(+) T-cell responses pre- and post-stimulation. Doxorubicin treatment alone had no effects on peripheral blood T lymphocytes and regulatory T-cells in vivo and in vitro. However, CD4(+) T-cells were resistant to doxorubicin and demonstrated more robust proliferation than CD8(+) T-cells after doxorubicin pre-treatment. CD40 ligand and 4-1BB expression on the surface of CD4(+) T-cells were increased after TCR-ligation activation; however, expression on CD8(+) T-cells was not increased. Dendritic cells cultured in the presence of activated CD4(+) T-cells pre-treated with doxorubicin had greater survival rates than those cultured with activated CD8(+) T-cells. Doxorubicin pre-treatment followed by anti-CD3epsilon+anti-4-1BB activation led to proliferation of CD4(+) T-cells and no proliferative effects on CD8(+) T-cells. Our results collectively suggest that doxorubicin pre-treatment in cancer patients may be a more effective way to enhance anti-cancer immune responses by increased antigen-specific CD4(+) Th1 immune responses.
Department of Anatomy, Chung-Ang University, College of Medicine, Seoul 156756, Republic of Korea.
Jae Yeo
JY
Park
Min Ja
MJ
Jang
Yoon Hee
YH
Chung
Kyung Yong
KY
Kim
Sung Su
SS
Kim
Won Bok
WB
Lee
Seungkwon
S
You
Youn Seok
YS
Choi
Dae Young
DY
Hur
Daejin
D
Kim
D053330:4-1BB Ligand / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D019470:Biolistics; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D023201:CD40 Ligand / Q000096:biosynthesis* / Q000235:genetics; D002470:Cell Survival; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage*; D005260:Female; D007114:Immunization; D051379:Mice; D008810:Mice, Inbred C57BL; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D053330:4-1BB Ligand; D015703:Antigens, CD; D023201:CD40 Ligand; D004317:Doxorubicin