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Sci Rep
2018 Jan 09;81:217. doi: 10.1038/s41598-017-18641-y.
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Combined SEP and anti-PD-L1 antibody produces a synergistic antitumor effect in B16-F10 melanoma-bearing mice.
Hu Z
,
Ye L
,
Xing Y
,
Hu J
,
Xi T
.
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The increased PD-L1 induces poorer prognosis in melanoma. The treatment with PD-1/PD-L1 antibodies have a low response rate. The combination immunotherapies are the encouraging drug development strategy to receive maximal therapeutic benefit. In this study, we investigated the enhanced antitumor and immunomodulatory activity of combined SEP and αPD-L1 in B16-F10 melanoma-bearing mice. The results shown that combined SEP and αPD-L1 presented significant synergistic antitumor effects, increased the frequency of CD8+ and CD4+ T cells in spleen and tumor, cytotoxic activity of CTL in spleen, and IL-2 and IFN-γ levels in splenocytes and tumor. The combination treatment also produced synergistic increase in P-ERK1/2 level in spleen. Immunohistochemistry shown that SEP induced the PD-L1 expression in melanoma tissue possibly by promoting IFN-γ excretion, which led to the synergistic anti-tumor effects of aPD-L1 and SEP. Furthermore, in the purified T lymphocyte from the naive mice, the combination of SEP and αPD-L1 had more potent than SEP or αPD-L1 in promoting T lymphocyte proliferation and cytokines secretion including IL-2 and IFN-γ, at least partially by activating MEK/ERK pathway. Our study provides the scientific basis for a clinical trial that would involve combination of anti-PD-L1 mAb and SEP for sustained melanoma control.
Figure 7. Combination of SEP and αPD-L1 on the effects of PD-L1 expression in the tumor tissue in B16-F10-bearing mice. At the end of the experiment (day 16), the collected melanoma tumors were fixed in 4% paraformaldehyde for 24 h and then embedded in paraffin. Serial sections (4-μm) were prepared for ICH. All immunostained tumor sections were examined by light microscopy at a magnification of ×100. The PD-L1 expression was significantly induced by SEP compared with that in the control group (Fig. 7A,B). The αPD-L1 decreased the PD-L1 expression compared with that in the control group (Fig. 7A,C). Furhtermore, the results in the combination group shown that αPD-L1 could decrease the PD-L1 expression induced by SEP in cancer tissue (Fig. 7B,D).
Figure 8. Effects of SEP and αPD-L1 combination on MEK/ERK signaling pathway in T lymphocytes in vitro. The T cells from naïve mice were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum. After the cells were pretreated with/without MEK inhibitor PD98059 (40 μM) for 30 min, they were cultured with the aPD-L1 (10 nM) and/or SEP (50 μg/ml) with ConA (2 μg/ml) for additional 48 h. The T cells were collected and lysed in lysis buffer supplemented with a cocktail of protease and phosphatase inhibitors. Western blot analysis was conducted for the detection of P-ERK1/2 and ERK1/2 expression. αPD-L1 or SEP in combination with ConA significantly increased the ratios of P-ERK1/2 and ERK1/2 compared with ConA group (P < 0.05, respectively, n = 3). Furthermore, combination of SEP and αPD-L1 had more potent than SEP (P < 0.05, n = 3) or αPD-L1 (P < 0.05, n = 3). However, after the pretreatment with PD98059 for 30 min, the the increased ratios induced by SEP or/and αPD-L1 was partially decreased (P < 0.05, respectively, n = 3). The results were presented as mean ± SEM. a
P < 0.05 compared with control group. b
P < 0.05, compared with SEP and αPD-L1 combination group (group 4). c
P < 0.05, compared with SEP and αPD-L1 combination group after PD98059 pretreatment for 30 min (group 7). *
P < 0.05, group 2 compared with group 5; group 3 compared with group 6; group 4 compared with group 7.
Figure 9. Effects of MEK inhibitor on proliferation induced by SEP and αPD-L1 combination in T lymphocytes in vitro. The T cells from naïve mice were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum. After the cells were pretreated with/without MEK inhibitor PD98059 (40 μM) for 30 min, they were cultured with the aPD-L1 (10 nM) and/or SEP (50 μg/ml) with ConA (2 μg/ml) for additional 48 h. Then the cell survival was determined by CCK-8 method. αPD-L1 or SEP in combination with ConA significantly promoted T lymphocytes proliferation compared with ConA group (P < 0.05, respectively, n = 6). Furthermore, combination of SEP and αPD-L1 had more potent than SEP (P < 0.05, n = 6) or αPD-L1 (P < 0.05, n = 6). However, after the pretreatment with PD98059 for 30 min, the T cell proliferation induced by SEP or/and αPD-L1 was partially inhibited (P < 0.05, respectively, n = 6). The results were presented as mean ± SEM. a
P < 0.05 compared with control group. b
P < 0.05, compared with SEP and αPD-L1 combination group (group 4). c
P < 0.05, compared with SEP and αPD-L1 combination group after PD98059 pretreatment for 30 min (group 7). *
P < 0.05, group 2 compared with group 5; group 3 compared with group 6; group 4 compared with group 7.
Figure 10. Effects of MEK inhibitor on IFN-γ and IL-2 secretion induced by SEP and αPD-L1 combination in T lymphocytes in vitro. The T cells from naïve mice were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum. After the cells were pretreated with/without MEK inhibitor PD98059 (40 μM) for 30 min, they were cultured with the aPD-L1 (10 nM) and/or SEP (50 μg/ml) with ConA (2 μg/ml) for additional 48 h. The cell supernatants were collected, and IL-2 and IFN-γ levels were mesured by murine ELISA kits. αPD-L1 or SEP in combination with ConA significantly increased IL-2 and IFN-γ secretion (Fig. 10A,B) compared with ConA group (P < 0.05, respectively, n = 6). Furthermore, combination of SEP and αPD-L1 had more potent than SEP (P < 0.05, n = 6) or αPD-L1 (P < 0.05, n = 6). However, after the pretreatment with PD98059, the increased IL-2 and IFN-γ secretion in SEP or/and αPD-L1 groups was partially inhibited (Fig. 10A,B) (P < 0.05, respectively, n = 6). The results were presented as mean ± SEM. a
P < 0.05 compared with control group. b
P < 0.05, compared with SEP and αPD-L1 combination group (group 4). c
P < 0.05, compared with SEP and αPD-L1 combination group after PD98059 pretreatment for 30 min (group 7). *
P < 0.05, group 2 compared with group 5; group 3 compared with group 6; group 4 compared with group 7.
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