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

G Locafaro, G Andolfi, F Russo, L Cesana, A Spinelli, B Camisa, F Ciceri, A Lombardo, A Bondanza, MG Roncarolo, S Gregori

Research output: Contribution to journalArticle

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 (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.
Original languageEnglish
Pages (from-to)2254-2269
Number of pages16
JournalMolecular Therapy
Volume25
Issue number10
DOIs
Publication statusPublished - 2017

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Myeloid Leukemia
Regulatory T-Lymphocytes
HLA Antigens
Interleukin-10
Leukemia
Graft vs Host Disease
T-Lymphocytes
Transplants
Hematopoietic Stem Cell Transplantation
Blood Cells
Granzymes
Neoplasms
Histocompatibility Antigens Class I
Immunotherapy
Clinical Trials

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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 journalArticle

Locafaro, G, Andolfi, G, Russo, F, Cesana, L, Spinelli, A, Camisa, B, Ciceri, F, Lombardo, A, Bondanza, A, Roncarolo, MG & Gregori, S 2017, 'IL-10-Engineered Human CD4+ Tr1 Cells Eliminate Myeloid Leukemia in an HLA Class I-Dependent Mechanism', Molecular Therapy, vol. 25, no. 10, pp. 2254-2269. https://doi.org/10.1016/j.ymthe.2017.06.029
Locafaro, G ; Andolfi, G ; Russo, F ; Cesana, L ; Spinelli, A ; Camisa, B ; Ciceri, F ; Lombardo, A ; Bondanza, A ; Roncarolo, MG ; Gregori, S. / IL-10-Engineered Human CD4+ Tr1 Cells Eliminate Myeloid Leukemia in an HLA Class I-Dependent Mechanism. In: Molecular Therapy. 2017 ; Vol. 25, No. 10. pp. 2254-2269.
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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

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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.

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