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Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors.

Ni J, Miller M, Stojanovic A, Garbi N, Cerwenka A - J. Exp. Med. (2012)

Bottom Line: IL-12/15/18-preactivated NK cells accumulated in the tumor tissue and persisted at high cell numbers with potent effector function that required the presence of CD4+ T cells.Human IL-12/15/18-preactivated NK cells also displayed sustained effector function in vitro.Moreover, our results reveal an essential role of CD4+ T cell help for sustained antitumor activity by NK cells linking adaptive and innate immunity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Junior Research Group Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

ABSTRACT
Natural killer cell (NK cell)-based immunotherapy of cancer is hampered by the transient effector function of NK cells. Recently, mouse IL-12/15/18-preactivated NK cells were shown to persist with sustained effector function in vivo. Our study investigated the antitumor activity of such NK cells. A single injection of syngeneic IL-12/15/18-preactivated NK cells, but neither naive nor IL-15- or IL-2-pretreated NK cells, combined with irradiation substantially reduced growth of established mouse tumors. Radiation therapy (RT) was essential for the antitumor activity of transferred NK cells. IL-12/15/18-preactivated NK cells expressed high levels of IL-2Rα (CD25), and their rapid in vivo proliferation depended on IL-2 produced by CD4+ T cells. IL-12/15/18-preactivated NK cells accumulated in the tumor tissue and persisted at high cell numbers with potent effector function that required the presence of CD4+ T cells. RT greatly increased numbers and function of transferred NK cells. Human IL-12/15/18-preactivated NK cells also displayed sustained effector function in vitro. Our study provides a better understanding for the rational design of immunotherapies of cancer that incorporate NK cells. Moreover, our results reveal an essential role of CD4+ T cell help for sustained antitumor activity by NK cells linking adaptive and innate immunity.

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IL-12/15/18–preactivated NK cells persist in recipient mice. RMA-S tumor–bearing mice received RT and preactivated NK cells as described in Fig. 2 b. 11 or 90 d after NK transfer, the numbers of host and transferred NK cells were analyzed. (a) Host (CD45.1−) and transferred (CD45.1+) NK cells in spleen on day 11 are shown. Cells were gated on CD3ε−NK1.1+ NK cells, and one representative dot plot from each group is shown (top). Numbers indicate percentages of host and transferred NK cells. Numbers of NK cells are depicted in the bottom panels. Graphs indicate mean + SD (n = 5). Data are representative of two independent experiments. (b) Representative dot plots (n = 3) of host (CD45.1−) and transferred (CD45.1+) NK cells on day 90 after transfer of IL-12/15/18–preactivated NK cells are shown from spleen, blood, lung, and liver of animals that had rejected the tumors. Cells were gated on CD3ε−NK1.1+ NK cells. Data are representative of two independent experiments.
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fig3: IL-12/15/18–preactivated NK cells persist in recipient mice. RMA-S tumor–bearing mice received RT and preactivated NK cells as described in Fig. 2 b. 11 or 90 d after NK transfer, the numbers of host and transferred NK cells were analyzed. (a) Host (CD45.1−) and transferred (CD45.1+) NK cells in spleen on day 11 are shown. Cells were gated on CD3ε−NK1.1+ NK cells, and one representative dot plot from each group is shown (top). Numbers indicate percentages of host and transferred NK cells. Numbers of NK cells are depicted in the bottom panels. Graphs indicate mean + SD (n = 5). Data are representative of two independent experiments. (b) Representative dot plots (n = 3) of host (CD45.1−) and transferred (CD45.1+) NK cells on day 90 after transfer of IL-12/15/18–preactivated NK cells are shown from spleen, blood, lung, and liver of animals that had rejected the tumors. Cells were gated on CD3ε−NK1.1+ NK cells. Data are representative of two independent experiments.

Mentions: Next, we analyzed transferred NK cells at later time points on day 11 and on day 90 after transfer into tumor-bearing, irradiated mice. Strikingly higher cell numbers of IL-12/15/18–preactivated NK cells were observed 11 d after transfer compared with IL-15–pretreated NK cells in spleen (Fig. 3 a) and tumor (not depicted). Of note, IL-12/15/18–preactivated NK cells were still detectable 3 mo after adoptive transfer in mice that had rejected the tumors and had remained tumor free. The transferred cells were detected in different organs such as spleen, blood, lung, liver (Fig. 3 b), and lymph node (not depicted). Overall, IL-12/15/18–preactivated NK cells can be recovered at high cell numbers after transfer in tumor-bearing, irradiated hosts and persist for at least 3 mo.


Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors.

Ni J, Miller M, Stojanovic A, Garbi N, Cerwenka A - J. Exp. Med. (2012)

IL-12/15/18–preactivated NK cells persist in recipient mice. RMA-S tumor–bearing mice received RT and preactivated NK cells as described in Fig. 2 b. 11 or 90 d after NK transfer, the numbers of host and transferred NK cells were analyzed. (a) Host (CD45.1−) and transferred (CD45.1+) NK cells in spleen on day 11 are shown. Cells were gated on CD3ε−NK1.1+ NK cells, and one representative dot plot from each group is shown (top). Numbers indicate percentages of host and transferred NK cells. Numbers of NK cells are depicted in the bottom panels. Graphs indicate mean + SD (n = 5). Data are representative of two independent experiments. (b) Representative dot plots (n = 3) of host (CD45.1−) and transferred (CD45.1+) NK cells on day 90 after transfer of IL-12/15/18–preactivated NK cells are shown from spleen, blood, lung, and liver of animals that had rejected the tumors. Cells were gated on CD3ε−NK1.1+ NK cells. Data are representative of two independent experiments.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3526364&req=5

fig3: IL-12/15/18–preactivated NK cells persist in recipient mice. RMA-S tumor–bearing mice received RT and preactivated NK cells as described in Fig. 2 b. 11 or 90 d after NK transfer, the numbers of host and transferred NK cells were analyzed. (a) Host (CD45.1−) and transferred (CD45.1+) NK cells in spleen on day 11 are shown. Cells were gated on CD3ε−NK1.1+ NK cells, and one representative dot plot from each group is shown (top). Numbers indicate percentages of host and transferred NK cells. Numbers of NK cells are depicted in the bottom panels. Graphs indicate mean + SD (n = 5). Data are representative of two independent experiments. (b) Representative dot plots (n = 3) of host (CD45.1−) and transferred (CD45.1+) NK cells on day 90 after transfer of IL-12/15/18–preactivated NK cells are shown from spleen, blood, lung, and liver of animals that had rejected the tumors. Cells were gated on CD3ε−NK1.1+ NK cells. Data are representative of two independent experiments.
Mentions: Next, we analyzed transferred NK cells at later time points on day 11 and on day 90 after transfer into tumor-bearing, irradiated mice. Strikingly higher cell numbers of IL-12/15/18–preactivated NK cells were observed 11 d after transfer compared with IL-15–pretreated NK cells in spleen (Fig. 3 a) and tumor (not depicted). Of note, IL-12/15/18–preactivated NK cells were still detectable 3 mo after adoptive transfer in mice that had rejected the tumors and had remained tumor free. The transferred cells were detected in different organs such as spleen, blood, lung, liver (Fig. 3 b), and lymph node (not depicted). Overall, IL-12/15/18–preactivated NK cells can be recovered at high cell numbers after transfer in tumor-bearing, irradiated hosts and persist for at least 3 mo.

Bottom Line: IL-12/15/18-preactivated NK cells accumulated in the tumor tissue and persisted at high cell numbers with potent effector function that required the presence of CD4+ T cells.Human IL-12/15/18-preactivated NK cells also displayed sustained effector function in vitro.Moreover, our results reveal an essential role of CD4+ T cell help for sustained antitumor activity by NK cells linking adaptive and innate immunity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Junior Research Group Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

ABSTRACT
Natural killer cell (NK cell)-based immunotherapy of cancer is hampered by the transient effector function of NK cells. Recently, mouse IL-12/15/18-preactivated NK cells were shown to persist with sustained effector function in vivo. Our study investigated the antitumor activity of such NK cells. A single injection of syngeneic IL-12/15/18-preactivated NK cells, but neither naive nor IL-15- or IL-2-pretreated NK cells, combined with irradiation substantially reduced growth of established mouse tumors. Radiation therapy (RT) was essential for the antitumor activity of transferred NK cells. IL-12/15/18-preactivated NK cells expressed high levels of IL-2Rα (CD25), and their rapid in vivo proliferation depended on IL-2 produced by CD4+ T cells. IL-12/15/18-preactivated NK cells accumulated in the tumor tissue and persisted at high cell numbers with potent effector function that required the presence of CD4+ T cells. RT greatly increased numbers and function of transferred NK cells. Human IL-12/15/18-preactivated NK cells also displayed sustained effector function in vitro. Our study provides a better understanding for the rational design of immunotherapies of cancer that incorporate NK cells. Moreover, our results reveal an essential role of CD4+ T cell help for sustained antitumor activity by NK cells linking adaptive and innate immunity.

Show MeSH
Related in: MedlinePlus