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 language | English (US) |
|---|---|
| Pages (from-to) | 323-336 |
| Number of pages | 14 |
| Journal | Cancer immunology research |
| Volume | 4 |
| Issue number | 4 |
| DOIs | |
| State | Published - 2016 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Immunology
- Cancer Research
Cite this
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 journal › Article
}
TY - JOUR
T1 - NK Cell-Mediated antitumor effects of a folate-conjugated immunoglobulin are enhanced by cytokines
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85016483007&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85016483007&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-15-0168
DO - 10.1158/2326-6066.CIR-15-0168
M3 - Article
C2 - 26865456
AN - SCOPUS:85016483007
VL - 4
SP - 323
EP - 336
JO - Cancer immunology research
JF - Cancer immunology research
SN - 2326-6066
IS - 4
ER -