Allogeneic effector/memory Th-1 cells impair FoxP3+ regulatory T lymphocytes and synergize with chaperone-rich cell lysate vaccine to treat leukemia.
Therapeutic strategies combining the induction of effective antitumor immunity with the inhibition of the mechanisms of tumor-induced immunosuppression represent a key objective in cancer immunotherapy. Herein we demonstrate that effector/memory CD4(+) T helper-1 (Th-1) lymphocytes, in addition to polarizing type-1 antitumor immune responses, impair tumor-induced CD4(+)CD25(+)FoxP3(+) regulatory T lymphocyte (Treg) immunosuppressive function in vitro and in vivo. Th-1 cells also inhibit the generation of FoxP3(+) Tregs from naive CD4(+)CD25(-)FoxP3(-) T cells by an interferon-γ-dependent mechanism. In addition, in an aggressive mouse leukemia model (12B1), Th-1 lymphocytes act synergistically with a chaperone-rich cell lysate (CRCL) vaccine, leading to improved survival and long-lasting protection against leukemia. The combination of CRCL as a source of tumor-specific antigens and Th-1 lymphocytes as an adjuvant has the potential to stimulate efficient specific antitumor immunity while restraining Treg-induced suppression.
Department of Pediatrics, Steele Children's Research Center, University of Arizona, 1501 N. Campbell Avenue, Tucson, AZ 85724-5073, USA.
Nona
N
Janikashvili
Collin J
CJ
LaCasse
Claire
C
Larmonier
Malika
M
Trad
Amanda
A
Herrell
Sara
S
Bustamante
Bernard
B
Bonnotte
Michael
M
Har-Noy
Nicolas
N
Larmonier
Emmanuel
E
Katsanis
D000818:Animals; D015153:Blotting, Western; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D002457:Cell Extracts / Q000008:administration & dosage* / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D007156:Immunologic Memory / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D007942:Leukemia, Experimental / Q000276:immunology / Q000628:therapy*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016513:Mice, SCID; D018832:Molecular Chaperones / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D019496:Cancer Vaccines; D002457:Cell Extracts; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018832:Molecular Chaperones; D007371:Interferon-gamma