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Mol Ther. 2017 Oct 4;25(10):2254-2269. doi: 10.1016/j.ymthe.2017.06.029. Epub 2017 Jul 5.

IL-10-Engineered Human CD4+ Tr1 Cells Eliminate Myeloid Leukemia in an HLA Class I-Dependent Mechanism.

Author information

1
San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
2
Experimental Imaging Centre, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
3
Innovative Immunotherapies Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
4
Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
5
San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan 20132, Italy; Vita Salute San Raffaele University, Milan 20132, Italy.
6
San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan 20132, Italy; Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, ISCBRM, Stanford School of Medicine, Stanford, CA 94305, USA. Electronic address: mg1@stanford.edu.
7
San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan 20132, Italy. Electronic address: gregori.silvia@hsr.it.

Abstract

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 (CD4IL-10) cells that suppress effector T cells in vitro and xenoGvHD in humanized mouse models. In the present study, we show that CD4IL-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 CD4IL-10 cells is granzyme B (GzB) dependent, is specific for CD13+ target cells, and requires CD54 and CD112 expression on primary leukemic target blasts. CD4IL-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), CD4IL-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 CD4IL-10 cell immunotherapy to prevent GvHD and promote GvL in allo-HSCT for myeloid malignancies.

KEYWORDS:

gene transfer; immunotherapy; tolerance

PMID:
28807569
PMCID:
PMC5628869
DOI:
10.1016/j.ymthe.2017.06.029
[Indexed for MEDLINE]
Free PMC Article

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