TY - JOUR
T1 - Human regulatory T cells do not suppress the antitumor immunity in the bone marrow
T2 - a role for bone marrow stromal cells in neutralizing regulatory T cells
AU - Guichelaar, Teun
AU - Emmelot, Maarten E
AU - Rozemuller, Henk
AU - Martini, Bianka
AU - Groen, Richard W J
AU - Storm, Gert
AU - Lokhorst, Henk M
AU - Martens, Anton C
AU - Mutis, Tuna
PY - 2013/3/15
Y1 - 2013/3/15
N2 - PURPOSE: Regulatory T cells (Tregs) are potent tools to prevent graft-versus-host disease (GVHD) induced after allogeneic stem cell transplantation or donor lymphocyte infusions. Toward clinical application of Tregs for GVHD treatment, we investigated the impact of Tregs on the therapeutic graft-versus-tumor (GVT) effect against human multiple myeloma tumors with various immunogenicities, progression rates, and localizations in a humanized murine model.EXPERIMENTAL DESIGN: Immunodeficient Rag2(-/-)γc(-/-) mice, bearing various human multiple myeloma tumors, were treated with human peripheral blood mononuclear cell (PBMC) alone or together with autologous ex vivo cultured Tregs. Mice were analyzed for the in vivo engraftment, homing of T-cell subsets, development of GVHD and GVT. In additional in vitro assays, Tregs that were cultured together with bone marrow stromal cells were analyzed for phenotype and functions.RESULTS: Treatment with PBMC alone induced variable degrees of antitumor response, depending on the immunogenicity and the growth rate of the tumor. Coinfusion of Tregs did not impair the antitumor response against tumors residing within the bone marrow, irrespective of their immunogenicity or growth rates. In contrast, Tregs readily inhibited the antitumor effect against tumors growing outside the bone marrow. Exploring this remarkable phenomenon, we discovered that bone marrow stroma neutralizes the suppressive activity of Tregs in part via production of interleukin (IL)-1β/IL-6. We furthermore found in vitro and in vivo evidence of conversion of Tregs into IL-17-producing T cells in the bone marrow environment.CONCLUSIONS: These results provide new insights into the Treg immunobiology and indicate the conditional benefits of future Treg-based therapies.
AB - PURPOSE: Regulatory T cells (Tregs) are potent tools to prevent graft-versus-host disease (GVHD) induced after allogeneic stem cell transplantation or donor lymphocyte infusions. Toward clinical application of Tregs for GVHD treatment, we investigated the impact of Tregs on the therapeutic graft-versus-tumor (GVT) effect against human multiple myeloma tumors with various immunogenicities, progression rates, and localizations in a humanized murine model.EXPERIMENTAL DESIGN: Immunodeficient Rag2(-/-)γc(-/-) mice, bearing various human multiple myeloma tumors, were treated with human peripheral blood mononuclear cell (PBMC) alone or together with autologous ex vivo cultured Tregs. Mice were analyzed for the in vivo engraftment, homing of T-cell subsets, development of GVHD and GVT. In additional in vitro assays, Tregs that were cultured together with bone marrow stromal cells were analyzed for phenotype and functions.RESULTS: Treatment with PBMC alone induced variable degrees of antitumor response, depending on the immunogenicity and the growth rate of the tumor. Coinfusion of Tregs did not impair the antitumor response against tumors residing within the bone marrow, irrespective of their immunogenicity or growth rates. In contrast, Tregs readily inhibited the antitumor effect against tumors growing outside the bone marrow. Exploring this remarkable phenomenon, we discovered that bone marrow stroma neutralizes the suppressive activity of Tregs in part via production of interleukin (IL)-1β/IL-6. We furthermore found in vitro and in vivo evidence of conversion of Tregs into IL-17-producing T cells in the bone marrow environment.CONCLUSIONS: These results provide new insights into the Treg immunobiology and indicate the conditional benefits of future Treg-based therapies.
KW - Animals
KW - Bone Marrow Cells/cytology
KW - Female
KW - Graft vs Host Disease/immunology
KW - Graft vs Tumor Effect
KW - Humans
KW - Interleukin-17/immunology
KW - Interleukin-6/immunology
KW - Leukocytes, Mononuclear/cytology
KW - Mice
KW - Multiple Myeloma/immunology
KW - Stromal Cells/cytology
KW - T-Lymphocyte Subsets/cytology
KW - T-Lymphocytes, Regulatory/cytology
KW - Transplantation, Homologous
U2 - 10.1158/1078-0432.CCR-12-2177
DO - 10.1158/1078-0432.CCR-12-2177
M3 - Article
C2 - 23382115
VL - 19
SP - 1467
EP - 1475
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 6
ER -