Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 2254-2269 |
| Number of pages | 16 |
| Journal | Molecular Therapy |
| Volume | 25 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 2017 |
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IL-10-Engineered Human CD4+ Tr1 Cells Eliminate Myeloid Leukemia in an HLA Class I-Dependent Mechanism. / Locafaro, G; Andolfi, G; Russo, F; Cesana, L; Spinelli, A; Camisa, B; Ciceri, F; Lombardo, A; Bondanza, A; Roncarolo, MG; Gregori, S.
In: Molecular Therapy, Vol. 25, No. 10, 2017, p. 2254-2269.Research output: Contribution to journal › Article
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TY - JOUR
T1 - IL-10-Engineered Human CD4+ Tr1 Cells Eliminate Myeloid Leukemia in an HLA Class I-Dependent Mechanism
AU - Locafaro, G
AU - Andolfi, G
AU - Russo, F
AU - Cesana, L
AU - Spinelli, A
AU - Camisa, B
AU - Ciceri, F
AU - Lombardo, A
AU - Bondanza, A
AU - Roncarolo, MG
AU - Gregori, S
PY - 2017
Y1 - 2017
N2 - T regulatory cells (Tregs) play a key role in modulating T cell responses. Clinical trials showed that Tregs modulate graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, their ability to mediate anti-leukemic activity (graft-versus-leukemia [GvL]) is largely unknown. Enforced interleukin-10 (IL-10) expression converts human CD4 + T cells into T regulatory type 1 (Tr1)-like (CD4 IL-10 ) cells that suppress effector T cells in vitro and xenoGvHD in humanized mouse models. In the present study, we show that CD4 IL-10 cells mediate anti-leukemic effects in vitro and in vivo in a human leukocyte antigen (HLA) class I-dependent but antigen-independent manner. The cytotoxicity mediated by CD4 IL-10 cells is granzyme B (GzB) dependent, is specific for CD13 + target cells, and requires CD54 and CD112 expression on primary leukemic target blasts. CD4 IL-10 cells adoptively transferred in humanized mouse models directly mediate anti-tumor and anti-leukemic effects. In addition, when co-transferred with peripheral blood mononuclear cells (PBMCs), CD4 IL-10 cells contribute to the GvL activity but suppress xenoGvHD mediated by the PBMCs. These findings provide for the first time a strong rationale for CD4 IL-10 cell immunotherapy to prevent GvHD and promote GvL in allo-HSCT for myeloid malignancies. Tr1 cells are generated by overexpressing IL-10 in CD4 + T cells (CD4 IL-10 ). In this issue of Molecular Therapy, Locafaro et al. (2017) show that CD4 IL-10 cells kill myeloid leukemia in an HLA class I-dependent mechanism, mediate anti-tumor and anti-leukemic effects, and contribute to GvL while preventing GvHD in humanized mice. © 2017.
AB - T regulatory cells (Tregs) play a key role in modulating T cell responses. Clinical trials showed that Tregs modulate graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, their ability to mediate anti-leukemic activity (graft-versus-leukemia [GvL]) is largely unknown. Enforced interleukin-10 (IL-10) expression converts human CD4 + T cells into T regulatory type 1 (Tr1)-like (CD4 IL-10 ) cells that suppress effector T cells in vitro and xenoGvHD in humanized mouse models. In the present study, we show that CD4 IL-10 cells mediate anti-leukemic effects in vitro and in vivo in a human leukocyte antigen (HLA) class I-dependent but antigen-independent manner. The cytotoxicity mediated by CD4 IL-10 cells is granzyme B (GzB) dependent, is specific for CD13 + target cells, and requires CD54 and CD112 expression on primary leukemic target blasts. CD4 IL-10 cells adoptively transferred in humanized mouse models directly mediate anti-tumor and anti-leukemic effects. In addition, when co-transferred with peripheral blood mononuclear cells (PBMCs), CD4 IL-10 cells contribute to the GvL activity but suppress xenoGvHD mediated by the PBMCs. These findings provide for the first time a strong rationale for CD4 IL-10 cell immunotherapy to prevent GvHD and promote GvL in allo-HSCT for myeloid malignancies. Tr1 cells are generated by overexpressing IL-10 in CD4 + T cells (CD4 IL-10 ). In this issue of Molecular Therapy, Locafaro et al. (2017) show that CD4 IL-10 cells kill myeloid leukemia in an HLA class I-dependent mechanism, mediate anti-tumor and anti-leukemic effects, and contribute to GvL while preventing GvHD in humanized mice. © 2017.
U2 - 10.1016/j.ymthe.2017.06.029
DO - 10.1016/j.ymthe.2017.06.029
M3 - Article
VL - 25
SP - 2254
EP - 2269
JO - Molecular Therapy
JF - Molecular Therapy
SN - 1525-0016
IS - 10
ER -