In vivo cyclophosphamide and IL-2 treatment impedes self-antigen-induced effector CD4 cell tolerization: implications for adoptive immunotherapy.
The development of T cell tolerance directed toward tumor-associated Ags can limit the repertoire of functional tumor-reactive T cells, thus impairing the ability of vaccines to elicit effective antitumor immunity. Adoptive immunotherapy strategies using ex vivo expanded tumor-reactive effector T cells can bypass this problem; however, the susceptibility of effector T cells to undergoing tolerization suggests that tolerance might also negatively impact adoptive immunotherapy. Nonetheless, adoptive immunotherapy strategies can be effective, particularly those utilizing the drug cyclophosphamide (CY) and/or exogenous IL-2. In the current study, we used a TCR-transgenic mouse adoptive transfer system to assess whether CY plus IL-2 treatment rescues effector CD4 cell function in the face of tolerizing Ag (i.e., cognate parenchymal self-Ag). CY plus IL-2 treatment not only enhances proliferation and accumulation of effector CD4 cells, but also preserves the ability of these cells to express the effector cytokine IFN-gamma (and to a lesser extent TNF-alpha) in proportion to the level of parenchymal self-Ag expression. When administered individually, CY but not IL-2 can markedly impede tolerization, although their combination is the most effective. Although effector CD4 cells in CY plus IL-2-treated self-Ag-expressing mice eventually succumb to tolerization, this delay results in an increased level of in situ IFN-gamma expression in cognate Ag-expressing parenchymal tissues as well as death via a mechanism that requires direct parenchymal Ag presentation. These results suggest that one potential mechanism by which CY and IL-2 augment adoptive immunotherapy strategies to treat cancer is by impeding the tolerization of tumor-reactive effector T cells.
Mihalyo
Marianne A
MA
Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut Health Center, Farmington, CT 06030, USA.
Doody
Amy D H
AD
McAleer
Jeremy P
JP
Nowak
Elizabeth C
EC
Long
Meixiao
M
Yang
Yi
Y
Adler
Adam J
AJ
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D001324:Autoantigens / Q000502:physiology*; D001327:Autoimmune Diseases / Q000276:immunology / Q000401:mortality / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation / Q000821:virology; D002999:Clone Cells; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000633:toxicity; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D016219:Immunotherapy, Adoptive / Q000379:methods; D007376:Interleukin-2 / Q000008:administration & dosage*; D007399:Interphase / Q000276:immunology; D008231:Lymphopenia / Q000139:chemically induced / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017634:Self Tolerance / Q000187:drug effects / Q000276:immunology*
D000276:Adjuvants, Immunologic; D001324:Autoantigens; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007376:Interleukin-2; D003520:Cyclophosphamide