Aminobisphosphonates prevent the inhibitory effects exerted by lymph node stromal cells on anti-tumor Vd 2 T lymphocytes in non-hodgkin lymphomas

Alessandra Musso, Silvia Catellani, Paolo Canevali, Sara Tavella, Roberta Venè, Silvia Boero, Ivana Pierri, Marco Gobbi, Annalisa Kunkl, Jean Louis Ravetti, Maria Raffaella Zocchi, Alessandro Poggi

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Abstract

In this study, we analyzed the influence of mesenchymal stromal cells derived from lymph nodes of non-Hodgkin's lymphomas, on effector functions and differentiation of Vdelta (6)2 T lymphocytes. We show that: i) lymph-node mesenchymal stromal cells of non-Hodgkin's lymphoma inhibit NKG2D-mediated lymphoid cell killing, but not rit-uximab-induced antibody-dependent cell-mediated cytotoxicity, exerted by V62 T lymphocytes; ii) pre-treatment of mesenchymal stromal cells with the aminobisphosphonates pamidronate or zoledronate can rescue lymphoma cell killing via NKG2D; iii) this is due to inhibition of transforming growth factor-p and increase in interleukin-15 production by mesenchymal stromal cells; iv) aminobisphosphonate-treated mesenchymal stromal cells drive V62 T-lym-phocyte differentiation into effector memory T cells, expressing the Thelper1 cytokines tumor necrosis factor-a and interferon-y. In non-Hodgkin's lymphoma lymph nodes, V62 T cells were mostly naïve; upon co-culture with autologous lymph-node mesenchymal stromal cells exposed to zoledronate, the percentage of terminal differentiated effector memory V62 T lymphocytes increased. In all non-Hodgkin's lymphomas, low or undetectable transcription of Thelper1 cytokines was found. In diffused large B-cell lymphomas and in a group of follicular lymphoma, transcription of transforming growth factor p and interleukin-10 was enhanced compared to non-neoplastic lymph nodes. Thus, in non-Hodgkin lymphomas mesenchymal stromal cells interfere with V62 T-lymphocyte cytolytic function and differentiation to Thelper1 and/or effector memory cells, depending on the prominent in situ cytokine milieu. Aminobisphosphonates, acting on lymph-node mesenchymal stromal cells, can push the balance towards Thelper1/effector memory and rescue the recognition and killing of lymphoma cells through NKG2D, sparing ritux-imab-induced antibody-dependent cell-mediated cytotoxicity.

Original languageEnglish
Pages (from-to)131-139
Number of pages9
JournalHaematologica
Volume99
Issue number1
DOIs
Publication statusPublished - Jan 1 2014

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Stromal Cells
Mesenchymal Stromal Cells
Non-Hodgkin's Lymphoma
Lymph Nodes
T-Lymphocytes
zoledronic acid
Neoplasms
Antibody-Dependent Cell Cytotoxicity
pamidronate
Transforming Growth Factors
Cytokines
Lymphoma
Interleukin-15
Follicular Lymphoma
B-Cell Lymphoma
Coculture Techniques
Interleukin-10
Interferons
Tumor Necrosis Factor-alpha
Lymphocytes

ASJC Scopus subject areas

  • Hematology

Cite this

Aminobisphosphonates prevent the inhibitory effects exerted by lymph node stromal cells on anti-tumor Vd 2 T lymphocytes in non-hodgkin lymphomas. / Musso, Alessandra; Catellani, Silvia; Canevali, Paolo; Tavella, Sara; Venè, Roberta; Boero, Silvia; Pierri, Ivana; Gobbi, Marco; Kunkl, Annalisa; Ravetti, Jean Louis; Zocchi, Maria Raffaella; Poggi, Alessandro.

In: Haematologica, Vol. 99, No. 1, 01.01.2014, p. 131-139.

Research output: Contribution to journalArticle

Musso, Alessandra ; Catellani, Silvia ; Canevali, Paolo ; Tavella, Sara ; Venè, Roberta ; Boero, Silvia ; Pierri, Ivana ; Gobbi, Marco ; Kunkl, Annalisa ; Ravetti, Jean Louis ; Zocchi, Maria Raffaella ; Poggi, Alessandro. / Aminobisphosphonates prevent the inhibitory effects exerted by lymph node stromal cells on anti-tumor Vd 2 T lymphocytes in non-hodgkin lymphomas. In: Haematologica. 2014 ; Vol. 99, No. 1. pp. 131-139.
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abstract = "In this study, we analyzed the influence of mesenchymal stromal cells derived from lymph nodes of non-Hodgkin's lymphomas, on effector functions and differentiation of Vdelta (6)2 T lymphocytes. We show that: i) lymph-node mesenchymal stromal cells of non-Hodgkin's lymphoma inhibit NKG2D-mediated lymphoid cell killing, but not rit-uximab-induced antibody-dependent cell-mediated cytotoxicity, exerted by V62 T lymphocytes; ii) pre-treatment of mesenchymal stromal cells with the aminobisphosphonates pamidronate or zoledronate can rescue lymphoma cell killing via NKG2D; iii) this is due to inhibition of transforming growth factor-p and increase in interleukin-15 production by mesenchymal stromal cells; iv) aminobisphosphonate-treated mesenchymal stromal cells drive V62 T-lym-phocyte differentiation into effector memory T cells, expressing the Thelper1 cytokines tumor necrosis factor-a and interferon-y. In non-Hodgkin's lymphoma lymph nodes, V62 T cells were mostly na{\"i}ve; upon co-culture with autologous lymph-node mesenchymal stromal cells exposed to zoledronate, the percentage of terminal differentiated effector memory V62 T lymphocytes increased. In all non-Hodgkin's lymphomas, low or undetectable transcription of Thelper1 cytokines was found. In diffused large B-cell lymphomas and in a group of follicular lymphoma, transcription of transforming growth factor p and interleukin-10 was enhanced compared to non-neoplastic lymph nodes. Thus, in non-Hodgkin lymphomas mesenchymal stromal cells interfere with V62 T-lymphocyte cytolytic function and differentiation to Thelper1 and/or effector memory cells, depending on the prominent in situ cytokine milieu. Aminobisphosphonates, acting on lymph-node mesenchymal stromal cells, can push the balance towards Thelper1/effector memory and rescue the recognition and killing of lymphoma cells through NKG2D, sparing ritux-imab-induced antibody-dependent cell-mediated cytotoxicity.",
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AU - Tavella, Sara

AU - Venè, Roberta

AU - Boero, Silvia

AU - Pierri, Ivana

AU - Gobbi, Marco

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AU - Poggi, Alessandro

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