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

Jing Ni, Matthias Miller, Ana Stojanovic, Natalio Garbi, Adelheid Cerwenka, Jing Ni, Matthias Miller, Ana Stojanovic, Natalio Garbi, Adelheid Cerwenka

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.

Figures

Figure 1.
Figure 1.
Adoptive transfer of IL-12/15/18–preactivated NK cells in combination with RT delays RMA-S tumor growth. (a) C57BL/6 mice were s.c. inoculated with 106 RMA-S tumor cells. After 7 d, tumor-bearing mice received 106 NK cells i.v. that were preactivated in vitro with IL-15 or IL-12/15/18 for 16 h. Tumor growth and survival were monitored. The graph of tumor growth displays mean + SEM (n = 5). Survival data are outlined from two experiments (n = 9, 5, and 10 for None, IL-15 NK, and IL-12/15/18 NK groups, respectively) and presented as a Kaplan–Meier survival curve. (b) RMA-S tumor–bearing mice were irradiated with 5 Gy of total body RT on day 7 after tumor cell inoculation. 106 IL-15– or IL-12/15/18–preactivated NK cells were transferred i.v. 3 h after irradiation. The graph of tumor growth displays mean + SEM (n = 5–8). Survival data are outlined from five experiments (n = 24, 38, 11, and 23 for None, RT, RT+IL-15 NK, and RT+IL-12/15/18 NK groups, respectively) and presented as a Kaplan–Meier survival curve. *, P < 0.05; and **, P < 0.01 compared with the group with RT treatment. (c) C57BL/6 mice (n = 10–12) were i.v. injected with 106 B16–RAE-1ε tumor cells and received RT and NK cell infusion (106) at day 7. Lungs were dissected at day 14 after tumor inoculation, and metastases were enumerated by counting the nodules. Numbers of lung metastases from individual mice are indicated, and their geometric mean values are shown. Nodules >500 are depicted as 500. Data are pooled from two independent experiments.
Figure 2.
Figure 2.
Adoptive transfer of IL-12/15/18–preactivated NK cells leads to high numbers of transferred NK cells in spleen and tumor. (a) C57BL/6 mice were inoculated with RMA-S tumor cells (day −7). Tumor-bearing mice received RT on day 0 or remained untreated as indicated. 4 d later, the numbers of CD3ε+CD4+, CD3ε+CD8+, CD3ε−NK1.1+, and CD4+FoxP3+ cells in spleen were determined. The graph indicates mean + SD (n = 3–6). Data are representative of two independent experiments. (b) C57BL/6 mice (CD45.2+) were inoculated with RMA-S tumor cells (day −7). Tumor-bearing mice received RT or remained nonirradiated and 106 IL-15– or IL-12/15/18–preactivated NK cells (CD45.1+) on day 0 as indicated. 4 d later, the numbers of host and transferred NK cells were analyzed. (c and d) Host (CD45.1−) and transferred (CD45.1+) NK cells in spleen (c) and tumor (d) are depicted. 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 in spleen and the percentages of NK cells among total cells in the tumor are depicted in the bottom panels. Graphs indicate mean + SD (n = 3). Data are representative of two independent experiments.
Figure 3.
Figure 3.
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.
Figure 4.
Figure 4.
Rapid proliferation of IL-12/15/18–preactivated NK cells in recipient mice is dependent on endogenous IL-2. NK cells (CD45.1+) were pretreated with IL-15 or IL-12/15/18 for 16 h and labeled with CFSE. RMA-S tumor–bearing mice received RT and 106 CFSE-labeled NK cells 3 h after irradiation as described in Fig. 2 b. (a) 4 d later, host and transferred cells were analyzed in the spleen, blood, lymph node, lung, liver, and tumor. The graph depicts the ratio between the numbers of transferred and host NK cells (mean + SD; n = 5). Data are representative of two independent experiments. (b) 4 d after transfer, in vivo proliferation of transferred NK cells was analyzed. Histograms were gated on CD3ε−NK1.1+CD45.1+ transferred NK cells, and one representative histogram from each group is shown (n = 5). Percentages of cells that proliferated are depicted. Data are representative of three independent experiments. (c) NK cells were treated with IL-15 or IL-12/15/18 for 16 h and stained with anti-CD25, -CD122, and -CD132 mAbs (bold black lines) or the isotype control (filled histograms). Data are representative of three independent experiments. (d) CFSE-labeled IL-12/15/18–pretreated NK cells (CD45.1+) were transferred into RMA-S tumor–bearing, irradiated mice (CD45.2+) as described in Fig. 2 b. Anti–IL-2, –IL-15, or –IL-12 mAb was applied as described in Materials and methods. 4 d after adoptive transfer, in vivo proliferation of transferred NK cells was analyzed. Cells were gated on CD3ε−NK1.1+CD45.1+ transferred NK cells, and one representative histogram from each group is shown (n = 3–5). The replication index indicating the fold expansion of the proliferating cells was calculated by FlowJo. Numbers of transferred NK cells in spleen are depicted. Graphs indicate mean + SD (n = 3–5). Data are representative of two independent experiments. (e) IL-2−/− mice or littermates (CD45.2+; top) and IL-15−/− or wild-type mice (CD45.2+; bottom) received RT and 106 CFSE-labeled preactivated NK cells (CD45.1+) 3 h after irradiation. 4 d later, CFSE dilution of transferred NK cells from spleen was determined. Data shown were gated on CD3ε−NK1.1+CD45.1+ transferred NK cells. One representative histogram from each group is shown (n = 3–5).
Figure 5.
Figure 5.
The rapid proliferation of IL-12/15/18–preactivated NK cells is dependent on CD4+T–producing IL-2. CFSE-labeled IL-12/15/18–pretreated NK (CD45.1+) cells were transferred into RMA-S tumor–bearing, irradiated mice (CD45.2+) as described in Fig. 2 b. Anti-CD4 or anti-CD8 mAb was applied as described in Materials and methods. 4 d later, spleen cells were analyzed. (a) Spleen cells were restimulated by PMA/ionomycin, and IL-2 expression was determined by intracellular staining. One representative dot plot gated on total splenocytes is shown. Numbers indicate percentages among total splenocytes. Percentages of IL-2–producing CD4+ or CD4− cells (after subtraction of the isotype control) in spleen are shown in the graph (mean + SD; n = 3). n.d., not detectable. Data are representative of three independent experiments. (b) CFSE-dilution in spleen was determined. Data shown were gated on CD3ε−NK1.1+CD45.1+ transferred NK cells, and one representative histogram from each group is shown (n = 3). The replication index of transferred NK cells was calculated by FlowJo. Numbers of transferred NK cells in spleen are shown. Graphs indicate mean + SD (n = 3). Data are representative of three independent experiments.
Figure 6.
Figure 6.
IL-12/15/18–preactivated NK cells display a mature phenotype before and after transfer. NK cells (CD45.1+) were treated with IL-15 or IL-12/15/18 for 16 h and transferred into tumor-bearing, irradiated mice (CD45.2+; n = 5) as described in Fig. 2 b. (a) Dot plots show the expression of CD11b and CD27 on splenic naive NK cells (gated on CD3ε−NK1.1+) and IL-15– or IL-12/15/18–preactivated NK cells before (gated on CD3ε−NK1.1+) and after transfer (gated on CD3ε−NK1.1+CD45.1+ transferred NK cells) on day 11. Numbers indicate percentages. (b) Histograms show expression of KLRG1 and CD43 on NK cells. Numbers indicate geometric mean fluorescence. All data are representative of two independent experiments.
Figure 7.
Figure 7.
IL-12/15/18–preactivated NK cells show high effector function before and after transfer into irradiated recipients. (a) NK cells were pretreated with IL-15 or IL-12/15/18 for 16 h. Expression of IFN-γ, granzyme B, and perforin (bold black lines) or the isotype control (filled histograms) was determined by flow cytometry. Data are representative of three independent experiments. (b and c) IL-15– or IL-12/15/18–pretreated NK cells (CD45.1+) were transferred into untreated (No RT) or irradiated (RT) tumor-bearing mice (CD45.2+) as described in Fig. 2 b. 4 d later, splenocytes were restimulated by RMA-S cells and stained with anti–IFN-γ, anti–granzyme B, and anti-perforin mAbs (bold black lines) or the isotype control (filled histograms; b). Dot plots (left) depict whole splenocytes. Histograms (right) are gated on CD45.1+NK1.1+ cells as indicated in the left panel. Numbers indicate percentages of IFN-γ–producing cells among the transferred NK cells or mean fluorescence intensity (MFI) of granzyme B and perforin expression. One representative dot plot or histogram from each group is shown. (c) Numbers of IFN-γ–producing transferred NK cells and mean fluorescence intensity of granzyme B and perforin detected in transferred NK cells are depicted. Graphs indicate mean + SD (n = 3). Data shown are representative of two independent experiments. (d) NK cells from wild-type, IFN-γ−/−, or perforin−/− mice were stimulated with IL-12/15/18 for 16 h and transferred into tumor-bearing, irradiated mice 7 d after tumor inoculation. Survival data are outlined from two experiments (n = 15, 9, 10, and 10 for RT, RT+NK wild-type, RT+NK IFN-γ−/−, and RT+NK perforin−/− groups, respectively) and presented as a Kaplan–Meier survival curve. ** , P < 0.01 compared with the other groups.
Figure 8.
Figure 8.
Host CD4+ T cells are indispensible for potent effector function and antitumor activity of IL-12/15/18–preactivated NK cells. (a and b) IL-12/15/18–pretreated NK cells (CD45.1+) were transferred into tumor-bearing, irradiated mice (CD45.2+) as described in Fig. 2 b. Anti-CD4 or anti-CD8 mAb was applied as described in Materials and methods. 11 d later, splenocytes were restimulated by RMA-S cells and stained for IFN-γ (a) or granzyme B (b). Dot plots and histograms shown are gated on CD3ε−NK1.1+ cells. Numbers indicate percentages among the host or transferred NK cells. One representative staining from each group is shown. Percentages of IFN-γ and levels of granzyme B produced by host (CD3ε−NK1.1+CD45.1−) and transferred (CD3ε−NK1.1+CD45.1+) NK cells are depicted in the bottom panels. Graphs indicate mean + SD (n = 3). Data shown are representative of two independent experiments. (c) NK cells were preactivated with IL-12/15/18 for 16 h and transferred into tumor-bearing, irradiated mice as described in Fig. 1 b. Anti-CD4 mAb was applied as described in Materials and methods. Tumor growth was monitored. Graphs display mean + SEM (n = 4–8). *, P < 0.05 compared with the group with RT treatment. Data shown are representative of two independent experiments. (d) Representative staining (n = 3) of frozen tumor sections obtained from mice 4 d after RT and transfer of IL-12/15/18–preactivated NK cells is depicted. Transferred NK cells and CD4+ and CD8+ T cells were stained with anti-CD45.1, anti-CD8, and anti-CD4 mAbs. Data shown are representative of two independent experiments. Bars, 25 µm.
Figure 9.
Figure 9.
IL-12/15/18–preactivated human NK cells show increased proliferation, cell recovery, and effector function compared with IL-15–pretreated cells. (a) Human NK cells were pretreated with IL-15 or IL-12/15/18 for 16 h, labeled with CFSE, and cultured in low-dose IL-2 (100 U/ml). In vitro proliferation and cell numbers were analyzed at the indicated time points. (b) CD25 expression on NK cells pretreated for 16 h with IL-15 or IL-12/15/18 is depicted. Isotype control is shown in the filled histograms; CD25 is shown by the bold black lines. (c) CFSE dilution was assessed on days 2, 4, and 6 of culture with IL-2. (d) Numbers of IL-2–cultured, IL-15– or IL-12/15/18–pretreated NK cells on days 0, 4, 6, and 8 of culture are depicted. Graph indicates mean + SD (cell counts from duplicate cultures). (e) IFN-γ production upon restimulation by IL-12/15 or K562 at an E/T ratio of 1:1 after culture for 4 or 8 d is shown. Supernatants were harvested after 24 h, and IFN-γ levels were determined by ELISA. Graph indicate mean + SD (duplicates from ELISA). (a–e) Data are representative of four independent donors.

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Source: PubMed

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