NK Cell-Mediated antitumor effects of a folate-conjugated immunoglobulin are enhanced by cytokines

Alena C. Jaime-Ramirez, Elizabeth L. McMichael, Sri Vidya Kondadasula, Cassandra C. Skinner, Bethany L. Mundy-Bosse, Eric Luedke, Natalie B. Jones, Aruna Mani, Julie Roda, Volodymyr Karpa, Hong Li, Jilong Li, Saranya Elavazhagan, Krista M. La Perle, Alessandra C. Schmitt, Yanhui Lu, Xiaoli Zhang, Xueliang Pan, Hsaioyin Mao, Melanie DavisDavid Jarjoura, Jonathan P. Butchar, Ming Poi, Mitch Phelps, Susheela Tridandapani, John C. Byrd, Michael A. Caligiuri, Robert J. Lee, William E. Carson

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Optimally effective antitumor therapies would not only activate immune effector cells but also engage them at the tumor. Folate conjugated to immunoglobulin (F-IgG) could direct innate immune cells with Fc receptors to folate receptor- expressing cancer cells. F-IgG bound to human KB and HeLa cells, as well as murine L1210JF, a folate receptor (FR)-overexpressing cancer cell line, as determined by flow cytometry. Recognition of F-IgG by natural killer (NK) cell Fc receptors led to phosphorylation of the ERK transcription factor and increased NK cell expression of CD69. Lysis of KB tumor cells by NK cells increased by about 5-fold after treatment with F-IgG, an effect synergistically enhanced by treatment with IL2, IL12, IL15, or IL21 (P < 0.001). F-IgG also enhanced the lysis of chronic lymphocytic leukemia cells by autologous NK cells. NK cells significantly increased production of IFNg, MIP-1a, and RANTES in response to F-IgG-coated KB target cells in the presence of the NK cell-activating cytokine IL12, and these coculture supernatants induced significant T-cell chemotaxis (P < 0.001). F-IgG-coated targets also stimulated FcR-mediated monocyte effector functions. Studies in a murine leukemia model confirmed the intratumoral localization and antitumor activity of F-IgG, as well as enhancement of its effects by IL12 (P = 0.05). The antitumor effect of this combination was dependent on NK cells and led to decreased tumor cell proliferation in vivo. Thus, F-IgG can induce an immune response against FR-positive tumor cells that is mediated by NK cells and can be augmented by cytokine therapy.

Original languageEnglish (US)
Pages (from-to)323-336
Number of pages14
JournalCancer immunology research
Volume4
Issue number4
DOIs
StatePublished - 2016
Externally publishedYes

Fingerprint

Folic Acid
Natural Killer Cells
Immunoglobulins
Immunoglobulin G
Cytokines
KB Cells
Interleukin-12
Neoplasms
Fc Receptors
Natural Killer Cell Receptors
Interleukin-15
Chemokine CCL5
Chemotaxis
B-Cell Chronic Lymphocytic Leukemia
Therapeutics
Coculture Techniques
Interleukin-2
Monocytes
Flow Cytometry
Leukemia

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Jaime-Ramirez, A. C., McMichael, E. L., Kondadasula, S. V., Skinner, C. C., Mundy-Bosse, B. L., Luedke, E., ... Carson, W. E. (2016). NK Cell-Mediated antitumor effects of a folate-conjugated immunoglobulin are enhanced by cytokines. Cancer immunology research, 4(4), 323-336. https://doi.org/10.1158/2326-6066.CIR-15-0168

NK Cell-Mediated antitumor effects of a folate-conjugated immunoglobulin are enhanced by cytokines. / Jaime-Ramirez, Alena C.; McMichael, Elizabeth L.; Kondadasula, Sri Vidya; Skinner, Cassandra C.; Mundy-Bosse, Bethany L.; Luedke, Eric; Jones, Natalie B.; Mani, Aruna; Roda, Julie; Karpa, Volodymyr; Li, Hong; Li, Jilong; Elavazhagan, Saranya; La Perle, Krista M.; Schmitt, Alessandra C.; Lu, Yanhui; Zhang, Xiaoli; Pan, Xueliang; Mao, Hsaioyin; Davis, Melanie; Jarjoura, David; Butchar, Jonathan P.; Poi, Ming; Phelps, Mitch; Tridandapani, Susheela; Byrd, John C.; Caligiuri, Michael A.; Lee, Robert J.; Carson, William E.

In: Cancer immunology research, Vol. 4, No. 4, 2016, p. 323-336.

Research output: Contribution to journalArticle

Jaime-Ramirez, AC, McMichael, EL, Kondadasula, SV, Skinner, CC, Mundy-Bosse, BL, Luedke, E, Jones, NB, Mani, A, Roda, J, Karpa, V, Li, H, Li, J, Elavazhagan, S, La Perle, KM, Schmitt, AC, Lu, Y, Zhang, X, Pan, X, Mao, H, Davis, M, Jarjoura, D, Butchar, JP, Poi, M, Phelps, M, Tridandapani, S, Byrd, JC, Caligiuri, MA, Lee, RJ & Carson, WE 2016, 'NK Cell-Mediated antitumor effects of a folate-conjugated immunoglobulin are enhanced by cytokines', Cancer immunology research, vol. 4, no. 4, pp. 323-336. https://doi.org/10.1158/2326-6066.CIR-15-0168
Jaime-Ramirez AC, McMichael EL, Kondadasula SV, Skinner CC, Mundy-Bosse BL, Luedke E et al. NK Cell-Mediated antitumor effects of a folate-conjugated immunoglobulin are enhanced by cytokines. Cancer immunology research. 2016;4(4):323-336. https://doi.org/10.1158/2326-6066.CIR-15-0168
Jaime-Ramirez, Alena C. ; McMichael, Elizabeth L. ; Kondadasula, Sri Vidya ; Skinner, Cassandra C. ; Mundy-Bosse, Bethany L. ; Luedke, Eric ; Jones, Natalie B. ; Mani, Aruna ; Roda, Julie ; Karpa, Volodymyr ; Li, Hong ; Li, Jilong ; Elavazhagan, Saranya ; La Perle, Krista M. ; Schmitt, Alessandra C. ; Lu, Yanhui ; Zhang, Xiaoli ; Pan, Xueliang ; Mao, Hsaioyin ; Davis, Melanie ; Jarjoura, David ; Butchar, Jonathan P. ; Poi, Ming ; Phelps, Mitch ; Tridandapani, Susheela ; Byrd, John C. ; Caligiuri, Michael A. ; Lee, Robert J. ; Carson, William E. / NK Cell-Mediated antitumor effects of a folate-conjugated immunoglobulin are enhanced by cytokines. In: Cancer immunology research. 2016 ; Vol. 4, No. 4. pp. 323-336.
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abstract = "Optimally effective antitumor therapies would not only activate immune effector cells but also engage them at the tumor. Folate conjugated to immunoglobulin (F-IgG) could direct innate immune cells with Fc receptors to folate receptor- expressing cancer cells. F-IgG bound to human KB and HeLa cells, as well as murine L1210JF, a folate receptor (FR)-overexpressing cancer cell line, as determined by flow cytometry. Recognition of F-IgG by natural killer (NK) cell Fc receptors led to phosphorylation of the ERK transcription factor and increased NK cell expression of CD69. Lysis of KB tumor cells by NK cells increased by about 5-fold after treatment with F-IgG, an effect synergistically enhanced by treatment with IL2, IL12, IL15, or IL21 (P < 0.001). F-IgG also enhanced the lysis of chronic lymphocytic leukemia cells by autologous NK cells. NK cells significantly increased production of IFNg, MIP-1a, and RANTES in response to F-IgG-coated KB target cells in the presence of the NK cell-activating cytokine IL12, and these coculture supernatants induced significant T-cell chemotaxis (P < 0.001). F-IgG-coated targets also stimulated FcR-mediated monocyte effector functions. Studies in a murine leukemia model confirmed the intratumoral localization and antitumor activity of F-IgG, as well as enhancement of its effects by IL12 (P = 0.05). The antitumor effect of this combination was dependent on NK cells and led to decreased tumor cell proliferation in vivo. Thus, F-IgG can induce an immune response against FR-positive tumor cells that is mediated by NK cells and can be augmented by cytokine therapy.",
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AU - Jaime-Ramirez, Alena C.

AU - McMichael, Elizabeth L.

AU - Kondadasula, Sri Vidya

AU - Skinner, Cassandra C.

AU - Mundy-Bosse, Bethany L.

AU - Luedke, Eric

AU - Jones, Natalie B.

AU - Mani, Aruna

AU - Roda, Julie

AU - Karpa, Volodymyr

AU - Li, Hong

AU - Li, Jilong

AU - Elavazhagan, Saranya

AU - La Perle, Krista M.

AU - Schmitt, Alessandra C.

AU - Lu, Yanhui

AU - Zhang, Xiaoli

AU - Pan, Xueliang

AU - Mao, Hsaioyin

AU - Davis, Melanie

AU - Jarjoura, David

AU - Butchar, Jonathan P.

AU - Poi, Ming

AU - Phelps, Mitch

AU - Tridandapani, Susheela

AU - Byrd, John C.

AU - Caligiuri, Michael A.

AU - Lee, Robert J.

AU - Carson, William E.

PY - 2016

Y1 - 2016

N2 - Optimally effective antitumor therapies would not only activate immune effector cells but also engage them at the tumor. Folate conjugated to immunoglobulin (F-IgG) could direct innate immune cells with Fc receptors to folate receptor- expressing cancer cells. F-IgG bound to human KB and HeLa cells, as well as murine L1210JF, a folate receptor (FR)-overexpressing cancer cell line, as determined by flow cytometry. Recognition of F-IgG by natural killer (NK) cell Fc receptors led to phosphorylation of the ERK transcription factor and increased NK cell expression of CD69. Lysis of KB tumor cells by NK cells increased by about 5-fold after treatment with F-IgG, an effect synergistically enhanced by treatment with IL2, IL12, IL15, or IL21 (P < 0.001). F-IgG also enhanced the lysis of chronic lymphocytic leukemia cells by autologous NK cells. NK cells significantly increased production of IFNg, MIP-1a, and RANTES in response to F-IgG-coated KB target cells in the presence of the NK cell-activating cytokine IL12, and these coculture supernatants induced significant T-cell chemotaxis (P < 0.001). F-IgG-coated targets also stimulated FcR-mediated monocyte effector functions. Studies in a murine leukemia model confirmed the intratumoral localization and antitumor activity of F-IgG, as well as enhancement of its effects by IL12 (P = 0.05). The antitumor effect of this combination was dependent on NK cells and led to decreased tumor cell proliferation in vivo. Thus, F-IgG can induce an immune response against FR-positive tumor cells that is mediated by NK cells and can be augmented by cytokine therapy.

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