Interleukin 15 provides relief to CTLs from regulatory T cell-mediated inhibition: Implications for adoptive T cell-based therapies for lymphoma

Serena K. Perna, Biagio De Angelis, Daria Pagliara, Sayyeda T. Hasan, Lan Zhang, Aruna Mahendravada, Helen E. Heslop, Malcolm K. Brenner, Cliona M. Rooney, Gianpietro Dotti, Barbara Savoldo

Research output: Contribution to journalArticle

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Abstract

Purpose: Systemic administration of recombinant interleukin (IL)-2 is used to support the expansion and persistence of adoptively transferred antigen-specific CTLs in patients with cancer. However, IL-2 also expands regulatory T cells (Treg) that in turn impair the antitumor activity of CTLs. As recombinant IL-15 is approaching clinical applications, we assessed the effects of this cytokine on the proliferation and antitumor activity of CTLs in the presence of Tregs.Weused the model of adoptive transfer of Epstein-Barr virus (EBV)-CTLs, as these cells induce responses in patients with EBV-associated Hodgkin lymphoma, and Tregs are frequently abundant in these patients. Experimental Design: Tregs were isolated from the peripheral blood of healthy donors and patients with Hodgkin lymphoma or from Hodgkin lymphoma tumors and assessed for their ability to inhibit the proliferation and antitumor activity of EBV-CTLs in the presence of IL-15 or IL-2. Specific molecular pathways activated by IL-15 were also explored. Results: We found that in the presence of Tregs, IL-15, but not IL-2, promoted the proliferation, effector function, and resistance to apoptosis of effectors T cells and EBV-CTLs. IL-15 did not reverse or block Tregs but instead preferentially supported the proliferation of CTLs and effector T cells as compared with Tregs. Conclusions: IL-15 selectively favors the survival, proliferation, and effector function of antigen-specific CTLs in the presence of Tregs, and thus IL-15, unlike IL-2, would have a significant impact in sustaining expansion and persistence of adoptively transferred CTLs in patients with cancer, including those infused with EBV-CTLs for treatment of EBV-associated malignancies.

Original languageEnglish
Pages (from-to)106-117
Number of pages12
JournalClinical Cancer Research
Volume19
Issue number1
DOIs
Publication statusPublished - Jan 1 2013

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Interleukin-15
Regulatory T-Lymphocytes
Cell- and Tissue-Based Therapy
Human Herpesvirus 4
Lymphoma
T-Lymphocytes
Interleukin-2
Hodgkin Disease
Neoplasms
Antigens
Adoptive Transfer
Blood Donors
Research Design
Apoptosis
Cytokines
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Interleukin 15 provides relief to CTLs from regulatory T cell-mediated inhibition : Implications for adoptive T cell-based therapies for lymphoma. / Perna, Serena K.; De Angelis, Biagio; Pagliara, Daria; Hasan, Sayyeda T.; Zhang, Lan; Mahendravada, Aruna; Heslop, Helen E.; Brenner, Malcolm K.; Rooney, Cliona M.; Dotti, Gianpietro; Savoldo, Barbara.

In: Clinical Cancer Research, Vol. 19, No. 1, 01.01.2013, p. 106-117.

Research output: Contribution to journalArticle

Perna, Serena K. ; De Angelis, Biagio ; Pagliara, Daria ; Hasan, Sayyeda T. ; Zhang, Lan ; Mahendravada, Aruna ; Heslop, Helen E. ; Brenner, Malcolm K. ; Rooney, Cliona M. ; Dotti, Gianpietro ; Savoldo, Barbara. / Interleukin 15 provides relief to CTLs from regulatory T cell-mediated inhibition : Implications for adoptive T cell-based therapies for lymphoma. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 1. pp. 106-117.
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AU - Pagliara, Daria

AU - Hasan, Sayyeda T.

AU - Zhang, Lan

AU - Mahendravada, Aruna

AU - Heslop, Helen E.

AU - Brenner, Malcolm K.

AU - Rooney, Cliona M.

AU - Dotti, Gianpietro

AU - Savoldo, Barbara

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N2 - Purpose: Systemic administration of recombinant interleukin (IL)-2 is used to support the expansion and persistence of adoptively transferred antigen-specific CTLs in patients with cancer. However, IL-2 also expands regulatory T cells (Treg) that in turn impair the antitumor activity of CTLs. As recombinant IL-15 is approaching clinical applications, we assessed the effects of this cytokine on the proliferation and antitumor activity of CTLs in the presence of Tregs.Weused the model of adoptive transfer of Epstein-Barr virus (EBV)-CTLs, as these cells induce responses in patients with EBV-associated Hodgkin lymphoma, and Tregs are frequently abundant in these patients. Experimental Design: Tregs were isolated from the peripheral blood of healthy donors and patients with Hodgkin lymphoma or from Hodgkin lymphoma tumors and assessed for their ability to inhibit the proliferation and antitumor activity of EBV-CTLs in the presence of IL-15 or IL-2. Specific molecular pathways activated by IL-15 were also explored. Results: We found that in the presence of Tregs, IL-15, but not IL-2, promoted the proliferation, effector function, and resistance to apoptosis of effectors T cells and EBV-CTLs. IL-15 did not reverse or block Tregs but instead preferentially supported the proliferation of CTLs and effector T cells as compared with Tregs. Conclusions: IL-15 selectively favors the survival, proliferation, and effector function of antigen-specific CTLs in the presence of Tregs, and thus IL-15, unlike IL-2, would have a significant impact in sustaining expansion and persistence of adoptively transferred CTLs in patients with cancer, including those infused with EBV-CTLs for treatment of EBV-associated malignancies.

AB - Purpose: Systemic administration of recombinant interleukin (IL)-2 is used to support the expansion and persistence of adoptively transferred antigen-specific CTLs in patients with cancer. However, IL-2 also expands regulatory T cells (Treg) that in turn impair the antitumor activity of CTLs. As recombinant IL-15 is approaching clinical applications, we assessed the effects of this cytokine on the proliferation and antitumor activity of CTLs in the presence of Tregs.Weused the model of adoptive transfer of Epstein-Barr virus (EBV)-CTLs, as these cells induce responses in patients with EBV-associated Hodgkin lymphoma, and Tregs are frequently abundant in these patients. Experimental Design: Tregs were isolated from the peripheral blood of healthy donors and patients with Hodgkin lymphoma or from Hodgkin lymphoma tumors and assessed for their ability to inhibit the proliferation and antitumor activity of EBV-CTLs in the presence of IL-15 or IL-2. Specific molecular pathways activated by IL-15 were also explored. Results: We found that in the presence of Tregs, IL-15, but not IL-2, promoted the proliferation, effector function, and resistance to apoptosis of effectors T cells and EBV-CTLs. IL-15 did not reverse or block Tregs but instead preferentially supported the proliferation of CTLs and effector T cells as compared with Tregs. Conclusions: IL-15 selectively favors the survival, proliferation, and effector function of antigen-specific CTLs in the presence of Tregs, and thus IL-15, unlike IL-2, would have a significant impact in sustaining expansion and persistence of adoptively transferred CTLs in patients with cancer, including those infused with EBV-CTLs for treatment of EBV-associated malignancies.

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