Microenvironmental regulation of the IL-23R/IL-23 axis overrides chronic lymphocytic leukemia indolence

Giovanna Cutrona; Claudio Tripodo; Serena Matis; Anna Grazia Recchia; Carlotta Massucco; Marina Fabbi; Monica Colombo; Laura Emionite; Sabina Sangaletti; Alessandro Gulino; Daniele Reverberi; Rosanna Massara; Simona Boccardo; Daniela de Totero; Sandra Salvi; Michele Cilli; Mariavaleria Pellicanò; Martina Manzoni; Sonia Fabris; Irma Airoldi; Francesca Valdora; Silvano Ferrini; Massimo Gentile; Ernesto Vigna; Sabrina Bossio; Laura De Stefano; Angela Palummo; Giovanni Iaquinta; Martina Cardillo; Simonetta Zupo; Giannamaria Cerruti; Adalberto Ibatici; Antonino Neri; Franco Fais; Manlio Ferrarini; Fortunato Morabito

doi:10.1126/scitranslmed.aal1571

Microenvironmental regulation of the IL-23R/IL-23 axis overrides chronic lymphocytic leukemia indolence

Giovanna Cutrona, Claudio Tripodo, Serena Matis, Anna Grazia Recchia, Carlotta Massucco, Marina Fabbi, Monica Colombo, Laura Emionite, Sabina Sangaletti, Alessandro Gulino, Daniele Reverberi, Rosanna Massara, Simona Boccardo, Daniela de Totero, Sandra Salvi, Michele Cilli, Mariavaleria Pellicanò, Martina Manzoni, Sonia Fabris, Irma AiroldiFrancesca Valdora, Silvano Ferrini, Massimo Gentile, Ernesto Vigna, Sabrina Bossio, Laura De Stefano, Angela Palummo, Giovanni Iaquinta, Martina Cardillo, Simonetta Zupo, Giannamaria Cerruti, Adalberto Ibatici, Antonino Neri, Franco Fais, Manlio Ferrarini, Fortunato Morabito

Research output: Contribution to journal › Article › peer-review

Abstract

Although the progression of chronic lymphocytic leukemia (CLL) requires the cooperation of the microenvironment, the exact cellular and molecular mechanisms involved are still unclear. We investigated the interleukin (IL)-23 receptor (IL-23R)/IL-23 axis and found that circulating cells from early-stage CLL patients with shorter time-to-treatment, but not of those with a more benign course, expressed a defective form of the IL-23R complex lacking the IL-12Rβ1 chain. However, cells from both patient groups expressed the complete IL-23R complex in tissue infiltrates and could be induced to express the IL-12Rβ1 chain when cocultured with activated T cells or CD40L+ cells. CLL cells activated in vitro in this context produced IL-23, a finding that, together with the presence of IL-23 in CLL lymphoid tissues, suggests the existence of an autocrine/paracrine loop inducing CLL cell proliferation. Interference with the IL-23R/IL-23 axis using an anti-IL-23p19 antibody proved effective in controlling disease onset and expansion in xenografted mice, suggesting potential therapeutic strategies.

Original language	English
Journal	Science Translational Medicine
Volume	10
Issue number	428
DOIs	https://doi.org/10.1126/scitranslmed.aal1571
Publication status	Published - Feb 14 2018

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Cutrona, G., Tripodo, C., Matis, S., Recchia, A. G., Massucco, C., Fabbi, M., Colombo, M., Emionite, L., Sangaletti, S., Gulino, A., Reverberi, D., Massara, R., Boccardo, S., de Totero, D., Salvi, S., Cilli, M., Pellicanò, M., Manzoni, M., Fabris, S., ... Morabito, F. (2018). Microenvironmental regulation of the IL-23R/IL-23 axis overrides chronic lymphocytic leukemia indolence. Science Translational Medicine, 10(428). https://doi.org/10.1126/scitranslmed.aal1571

Cutrona, G, Tripodo, C, Matis, S, Recchia, AG, Massucco, C, Fabbi, M, Colombo, M, Emionite, L , Sangaletti, S, Gulino, A, Reverberi, D, Massara, R, Boccardo, S, de Totero, D, Salvi, S, Cilli, M, Pellicanò, M, Manzoni, M , Fabris, S , Airoldi, I, Valdora, F, Ferrini, S, Gentile, M, Vigna, E, Bossio, S, De Stefano, L, Palummo, A, Iaquinta, G, Cardillo, M, Zupo, S, Cerruti, G, Ibatici, A , Neri, A , Fais, F, Ferrarini, M & Morabito, F 2018, 'Microenvironmental regulation of the IL-23R/IL-23 axis overrides chronic lymphocytic leukemia indolence', Science Translational Medicine, vol. 10, no. 428. https://doi.org/10.1126/scitranslmed.aal1571

@article{c8e638222c7a4c24b2322b65099b6c5f,

title = "Microenvironmental regulation of the IL-23R/IL-23 axis overrides chronic lymphocytic leukemia indolence",

abstract = "Although the progression of chronic lymphocytic leukemia (CLL) requires the cooperation of the microenvironment, the exact cellular and molecular mechanisms involved are still unclear. We investigated the interleukin (IL)-23 receptor (IL-23R)/IL-23 axis and found that circulating cells from early-stage CLL patients with shorter time-to-treatment, but not of those with a more benign course, expressed a defective form of the IL-23R complex lacking the IL-12Rβ1 chain. However, cells from both patient groups expressed the complete IL-23R complex in tissue infiltrates and could be induced to express the IL-12Rβ1 chain when cocultured with activated T cells or CD40L+ cells. CLL cells activated in vitro in this context produced IL-23, a finding that, together with the presence of IL-23 in CLL lymphoid tissues, suggests the existence of an autocrine/paracrine loop inducing CLL cell proliferation. Interference with the IL-23R/IL-23 axis using an anti-IL-23p19 antibody proved effective in controlling disease onset and expansion in xenografted mice, suggesting potential therapeutic strategies.",

author = "Giovanna Cutrona and Claudio Tripodo and Serena Matis and Recchia, {Anna Grazia} and Carlotta Massucco and Marina Fabbi and Monica Colombo and Laura Emionite and Sabina Sangaletti and Alessandro Gulino and Daniele Reverberi and Rosanna Massara and Simona Boccardo and {de Totero}, Daniela and Sandra Salvi and Michele Cilli and Mariavaleria Pellican{\`o} and Martina Manzoni and Sonia Fabris and Irma Airoldi and Francesca Valdora and Silvano Ferrini and Massimo Gentile and Ernesto Vigna and Sabrina Bossio and {De Stefano}, Laura and Angela Palummo and Giovanni Iaquinta and Martina Cardillo and Simonetta Zupo and Giannamaria Cerruti and Adalberto Ibatici and Antonino Neri and Franco Fais and Manlio Ferrarini and Fortunato Morabito",

note = "Copyright {\textcopyright} 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.",

year = "2018",

month = feb,

day = "14",

doi = "10.1126/scitranslmed.aal1571",

language = "English",

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T1 - Microenvironmental regulation of the IL-23R/IL-23 axis overrides chronic lymphocytic leukemia indolence

AU - Cutrona, Giovanna

AU - Tripodo, Claudio

AU - Matis, Serena

AU - Recchia, Anna Grazia

AU - Massucco, Carlotta

AU - Fabbi, Marina

AU - Colombo, Monica

AU - Emionite, Laura

AU - Sangaletti, Sabina

AU - Gulino, Alessandro

AU - Reverberi, Daniele

AU - Massara, Rosanna

AU - Boccardo, Simona

AU - de Totero, Daniela

AU - Salvi, Sandra

AU - Cilli, Michele

AU - Pellicanò, Mariavaleria

AU - Manzoni, Martina

AU - Fabris, Sonia

AU - Airoldi, Irma

AU - Valdora, Francesca

AU - Ferrini, Silvano

AU - Gentile, Massimo

AU - Vigna, Ernesto

AU - Bossio, Sabrina

AU - De Stefano, Laura

AU - Palummo, Angela

AU - Iaquinta, Giovanni

AU - Cardillo, Martina

AU - Zupo, Simonetta

AU - Cerruti, Giannamaria

AU - Ibatici, Adalberto

AU - Neri, Antonino

AU - Fais, Franco

AU - Ferrarini, Manlio

AU - Morabito, Fortunato

PY - 2018/2/14

Y1 - 2018/2/14

N2 - Although the progression of chronic lymphocytic leukemia (CLL) requires the cooperation of the microenvironment, the exact cellular and molecular mechanisms involved are still unclear. We investigated the interleukin (IL)-23 receptor (IL-23R)/IL-23 axis and found that circulating cells from early-stage CLL patients with shorter time-to-treatment, but not of those with a more benign course, expressed a defective form of the IL-23R complex lacking the IL-12Rβ1 chain. However, cells from both patient groups expressed the complete IL-23R complex in tissue infiltrates and could be induced to express the IL-12Rβ1 chain when cocultured with activated T cells or CD40L+ cells. CLL cells activated in vitro in this context produced IL-23, a finding that, together with the presence of IL-23 in CLL lymphoid tissues, suggests the existence of an autocrine/paracrine loop inducing CLL cell proliferation. Interference with the IL-23R/IL-23 axis using an anti-IL-23p19 antibody proved effective in controlling disease onset and expansion in xenografted mice, suggesting potential therapeutic strategies.

AB - Although the progression of chronic lymphocytic leukemia (CLL) requires the cooperation of the microenvironment, the exact cellular and molecular mechanisms involved are still unclear. We investigated the interleukin (IL)-23 receptor (IL-23R)/IL-23 axis and found that circulating cells from early-stage CLL patients with shorter time-to-treatment, but not of those with a more benign course, expressed a defective form of the IL-23R complex lacking the IL-12Rβ1 chain. However, cells from both patient groups expressed the complete IL-23R complex in tissue infiltrates and could be induced to express the IL-12Rβ1 chain when cocultured with activated T cells or CD40L+ cells. CLL cells activated in vitro in this context produced IL-23, a finding that, together with the presence of IL-23 in CLL lymphoid tissues, suggests the existence of an autocrine/paracrine loop inducing CLL cell proliferation. Interference with the IL-23R/IL-23 axis using an anti-IL-23p19 antibody proved effective in controlling disease onset and expansion in xenografted mice, suggesting potential therapeutic strategies.

U2 - 10.1126/scitranslmed.aal1571

DO - 10.1126/scitranslmed.aal1571

M3 - Article

C2 - 29444977

SN - 1946-6234

VL - 10

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 428

ER -

Microenvironmental regulation of the IL-23R/IL-23 axis overrides chronic lymphocytic leukemia indolence

Abstract

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