161533 TriKE stimulates NK-cell function to overcome myeloid-derived suppressor cells in MDS

Dhifaf Akef Sarhan, Ludwig Brandt, Martin Felices, Karolin Guldevall, Todd R Lenvik, Peter Hinderlie, Julie M Curtsinger, Erica D Warlick, Stephen R. Spellman, Bruce R Blazar, Daniel J Weisdorf, Sarah A Cooley, Daniel A Vallera, Björn Onfelt, Jeffrey S Miller

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Myelodysplastic syndrome (MDS) is a clonal heterogeneous stem cell disorder driven by multiple genetic and epigenetic alterations resulting in ineffective hematopoiesis. MDS has a high frequency of immune suppressors, including myeloid-derived suppressor cells (MDSCs), that collectively result in a poor immune response. MDSCs in MDS patients express CD155 that ligates the T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and delivers an inhibitory signal to natural killer (NK) cells. To mediate a productive immune response against MDS, negative regulatory checkpoints, like TIGIT, expressed on MDS NK cells must be overcome. NK cells can be directed to lyse MDS cells by bispecific killer engagers (BiKEs) that ligate CD16 on NK cells and CD33 on MDS cells. However, such CD16 3 CD33 (1633) BiKEs do not induce the proliferative response in MDS NK cells needed to sustain their function. Here, we show that the addition of an NK stimulatory cytokine, interleukin-15 (IL-15), into the BiKE platform leads to productive IL-15 signaling without TIGIT upregulation on NK cells from MDS patients. Lower TIGIT expression allowed NK cells to resist MDSC inhibition. When compared with 1633 BiKE, 161533 trispecific killer engager (TriKE)–treated NK cells demonstrated superior killing kinetics associated with increased STAT5 phosphorylation. Furthermore, 161533 TriKE–treated MDS NK cells had higher proliferation and enhanced NK-cell function than 1633 BiKE–treated cells without the IL-15 linker. Collectively, our data demonstrate novel characteristics of the 161533 TriKE that support its application as an immunotherapeutic agent for MDS patients.

Original languageEnglish (US)
Pages (from-to)1459-1469
Number of pages11
JournalBlood Advances
Volume2
Issue number12
DOIs
StatePublished - Jun 26 2018

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Myelodysplastic Syndromes
Natural Killer Cells
Interleukin-15
Myeloid-Derived Suppressor Cells
Hematopoiesis
Epigenomics
Up-Regulation
Stem Cells
Phosphorylation
Cytokines
T-Lymphocytes

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

Cite this

161533 TriKE stimulates NK-cell function to overcome myeloid-derived suppressor cells in MDS. / Sarhan, Dhifaf Akef; Brandt, Ludwig; Felices, Martin; Guldevall, Karolin; Lenvik, Todd R; Hinderlie, Peter; Curtsinger, Julie M; Warlick, Erica D; Spellman, Stephen R.; Blazar, Bruce R; Weisdorf, Daniel J; Cooley, Sarah A; Vallera, Daniel A; Onfelt, Björn; Miller, Jeffrey S.

In: Blood Advances, Vol. 2, No. 12, 26.06.2018, p. 1459-1469.

Research output: Contribution to journalArticle

Sarhan, Dhifaf Akef ; Brandt, Ludwig ; Felices, Martin ; Guldevall, Karolin ; Lenvik, Todd R ; Hinderlie, Peter ; Curtsinger, Julie M ; Warlick, Erica D ; Spellman, Stephen R. ; Blazar, Bruce R ; Weisdorf, Daniel J ; Cooley, Sarah A ; Vallera, Daniel A ; Onfelt, Björn ; Miller, Jeffrey S. / 161533 TriKE stimulates NK-cell function to overcome myeloid-derived suppressor cells in MDS. In: Blood Advances. 2018 ; Vol. 2, No. 12. pp. 1459-1469.
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abstract = "Myelodysplastic syndrome (MDS) is a clonal heterogeneous stem cell disorder driven by multiple genetic and epigenetic alterations resulting in ineffective hematopoiesis. MDS has a high frequency of immune suppressors, including myeloid-derived suppressor cells (MDSCs), that collectively result in a poor immune response. MDSCs in MDS patients express CD155 that ligates the T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and delivers an inhibitory signal to natural killer (NK) cells. To mediate a productive immune response against MDS, negative regulatory checkpoints, like TIGIT, expressed on MDS NK cells must be overcome. NK cells can be directed to lyse MDS cells by bispecific killer engagers (BiKEs) that ligate CD16 on NK cells and CD33 on MDS cells. However, such CD16 3 CD33 (1633) BiKEs do not induce the proliferative response in MDS NK cells needed to sustain their function. Here, we show that the addition of an NK stimulatory cytokine, interleukin-15 (IL-15), into the BiKE platform leads to productive IL-15 signaling without TIGIT upregulation on NK cells from MDS patients. Lower TIGIT expression allowed NK cells to resist MDSC inhibition. When compared with 1633 BiKE, 161533 trispecific killer engager (TriKE)–treated NK cells demonstrated superior killing kinetics associated with increased STAT5 phosphorylation. Furthermore, 161533 TriKE–treated MDS NK cells had higher proliferation and enhanced NK-cell function than 1633 BiKE–treated cells without the IL-15 linker. Collectively, our data demonstrate novel characteristics of the 161533 TriKE that support its application as an immunotherapeutic agent for MDS patients.",
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AU - Sarhan, Dhifaf Akef

AU - Brandt, Ludwig

AU - Felices, Martin

AU - Guldevall, Karolin

AU - Lenvik, Todd R

AU - Hinderlie, Peter

AU - Curtsinger, Julie M

AU - Warlick, Erica D

AU - Spellman, Stephen R.

AU - Blazar, Bruce R

AU - Weisdorf, Daniel J

AU - Cooley, Sarah A

AU - Vallera, Daniel A

AU - Onfelt, Björn

AU - Miller, Jeffrey S

PY - 2018/6/26

Y1 - 2018/6/26

N2 - Myelodysplastic syndrome (MDS) is a clonal heterogeneous stem cell disorder driven by multiple genetic and epigenetic alterations resulting in ineffective hematopoiesis. MDS has a high frequency of immune suppressors, including myeloid-derived suppressor cells (MDSCs), that collectively result in a poor immune response. MDSCs in MDS patients express CD155 that ligates the T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and delivers an inhibitory signal to natural killer (NK) cells. To mediate a productive immune response against MDS, negative regulatory checkpoints, like TIGIT, expressed on MDS NK cells must be overcome. NK cells can be directed to lyse MDS cells by bispecific killer engagers (BiKEs) that ligate CD16 on NK cells and CD33 on MDS cells. However, such CD16 3 CD33 (1633) BiKEs do not induce the proliferative response in MDS NK cells needed to sustain their function. Here, we show that the addition of an NK stimulatory cytokine, interleukin-15 (IL-15), into the BiKE platform leads to productive IL-15 signaling without TIGIT upregulation on NK cells from MDS patients. Lower TIGIT expression allowed NK cells to resist MDSC inhibition. When compared with 1633 BiKE, 161533 trispecific killer engager (TriKE)–treated NK cells demonstrated superior killing kinetics associated with increased STAT5 phosphorylation. Furthermore, 161533 TriKE–treated MDS NK cells had higher proliferation and enhanced NK-cell function than 1633 BiKE–treated cells without the IL-15 linker. Collectively, our data demonstrate novel characteristics of the 161533 TriKE that support its application as an immunotherapeutic agent for MDS patients.

AB - Myelodysplastic syndrome (MDS) is a clonal heterogeneous stem cell disorder driven by multiple genetic and epigenetic alterations resulting in ineffective hematopoiesis. MDS has a high frequency of immune suppressors, including myeloid-derived suppressor cells (MDSCs), that collectively result in a poor immune response. MDSCs in MDS patients express CD155 that ligates the T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and delivers an inhibitory signal to natural killer (NK) cells. To mediate a productive immune response against MDS, negative regulatory checkpoints, like TIGIT, expressed on MDS NK cells must be overcome. NK cells can be directed to lyse MDS cells by bispecific killer engagers (BiKEs) that ligate CD16 on NK cells and CD33 on MDS cells. However, such CD16 3 CD33 (1633) BiKEs do not induce the proliferative response in MDS NK cells needed to sustain their function. Here, we show that the addition of an NK stimulatory cytokine, interleukin-15 (IL-15), into the BiKE platform leads to productive IL-15 signaling without TIGIT upregulation on NK cells from MDS patients. Lower TIGIT expression allowed NK cells to resist MDSC inhibition. When compared with 1633 BiKE, 161533 trispecific killer engager (TriKE)–treated NK cells demonstrated superior killing kinetics associated with increased STAT5 phosphorylation. Furthermore, 161533 TriKE–treated MDS NK cells had higher proliferation and enhanced NK-cell function than 1633 BiKE–treated cells without the IL-15 linker. Collectively, our data demonstrate novel characteristics of the 161533 TriKE that support its application as an immunotherapeutic agent for MDS patients.

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