Abstract:Summary
Interleukin-34 (IL-34) is an alternative ligand to colony-stimulating factor-1 (CSF-1) for the CSF-1 receptor that acts as a key regulator of monocyte/macrophage lineage. In this study, we show that tumor-derived IL-34 mediates resistance to immune checkpoint blockade regardless of CSF-1 existence in various murine cancer models. Consistent with its immunosuppressive characteristics, the expression of IL-34 in tumors correlates with decreased frequencies of cellular (such as CD8
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“… Figure 5 Outcome of immunotherapy in PDX mouse model (A) Tumor growth in Humanized NSG (HuNSG) mice inoculated with LU-TM-0007 tumor cells and treated with the antibodies (left). Body weight in HuNSG day after tumor injection (right), n = 3 per group (Figure reprinted with permission from Hama et al., 2020 ). (B) Macroscopic observation of the subcutaneously injected xenografts in HuNSG mice sacrificed on day 28.…”
Section: Expected Outcomesmentioning
confidence: 99%
“… (B) Macroscopic observation of the subcutaneously injected xenografts in HuNSG mice sacrificed on day 28. Combination therapy caused strong necrosis in one of the treated tumors (∗), which could not be further analyzed (Figure reprinted with permission from Hama et al., 2020 ). …”
Section: Expected Outcomesmentioning
confidence: 99%
“… (A) Tumor growth in Humanized NSG (HuNSG) mice inoculated with LU-TM-0007 tumor cells and treated with the antibodies (left). Body weight in HuNSG day after tumor injection (right), n = 3 per group (Figure reprinted with permission from Hama et al., 2020 ). …”
Section: Expected Outcomesmentioning
confidence: 99%
“…This model helps to determine the effect of IL-34 neutralization along with the immune checkpoint blockade in human tumors. For complete details on the use and execution of this protocol, please refer to Hama et al. (2020) .…”
mentioning
confidence: 99%
“…For complete details on the use and execution of this protocol, please refer to Hama et al. (2020) .…”
Summary
Previously, we identified a therapy-resistant role of IL-34 in an immune checkpoint blockade in murine models. To investigate whether a similar mechanism is applicable in human tumors as well, we used this protocol for the selection of IL-34-neutralizing antibody and transplanting human tumor tissue expressing both IL-34 and PD-L1 as a patient-derived xenograft in immunologically humanized mice. This model helps to determine the effect of IL-34 neutralization along with the immune checkpoint blockade in human tumors.
For complete details on the use and execution of this protocol, please refer to
Hama et al. (2020)
.
“… Figure 5 Outcome of immunotherapy in PDX mouse model (A) Tumor growth in Humanized NSG (HuNSG) mice inoculated with LU-TM-0007 tumor cells and treated with the antibodies (left). Body weight in HuNSG day after tumor injection (right), n = 3 per group (Figure reprinted with permission from Hama et al., 2020 ). (B) Macroscopic observation of the subcutaneously injected xenografts in HuNSG mice sacrificed on day 28.…”
Section: Expected Outcomesmentioning
confidence: 99%
“… (B) Macroscopic observation of the subcutaneously injected xenografts in HuNSG mice sacrificed on day 28. Combination therapy caused strong necrosis in one of the treated tumors (∗), which could not be further analyzed (Figure reprinted with permission from Hama et al., 2020 ). …”
Section: Expected Outcomesmentioning
confidence: 99%
“… (A) Tumor growth in Humanized NSG (HuNSG) mice inoculated with LU-TM-0007 tumor cells and treated with the antibodies (left). Body weight in HuNSG day after tumor injection (right), n = 3 per group (Figure reprinted with permission from Hama et al., 2020 ). …”
Section: Expected Outcomesmentioning
confidence: 99%
“…This model helps to determine the effect of IL-34 neutralization along with the immune checkpoint blockade in human tumors. For complete details on the use and execution of this protocol, please refer to Hama et al. (2020) .…”
mentioning
confidence: 99%
“…For complete details on the use and execution of this protocol, please refer to Hama et al. (2020) .…”
Summary
Previously, we identified a therapy-resistant role of IL-34 in an immune checkpoint blockade in murine models. To investigate whether a similar mechanism is applicable in human tumors as well, we used this protocol for the selection of IL-34-neutralizing antibody and transplanting human tumor tissue expressing both IL-34 and PD-L1 as a patient-derived xenograft in immunologically humanized mice. This model helps to determine the effect of IL-34 neutralization along with the immune checkpoint blockade in human tumors.
For complete details on the use and execution of this protocol, please refer to
Hama et al. (2020)
.
Hepatoblastoma is the most common pediatric liver tumor, but little research has been done on the role of macrophages in hepatoblastoma. The purpose of this study was to gain insight into potential roles for macrophages in hepatoblastoma. Paraffin-embedded specimens from 56 patients who underwent surgical resection were examined with immunohistochemical staining for the macrophage-specific markers, Iba1 and CD163. Significant differences were seen among histological subtypes. Significantly increased numbers of macrophages were detected in embryonal components compared to fetal components in the mixed epithelial type. In vitro studies using human monocyte-derived macrophages and two hepatoblastoma cell lines (HepG2 and Huh6) were performed.Conditioned medium from these cell lines induced increased CD163 expression in macrophages. Direct co-culture with macrophages induced tumor cell proliferation via induction of protumor cytokine secretion from macrophages. Direct co-culture with macrophages also induced interleukin (IL)-34 overexpression by Huh6 cells via Brd4 signaling. IL-34 overexpression promoted tumor cell proliferation and chemoresistance. High IL-34 and Brd4 expression was detected in embryonal components, which have potentially higher proliferation activity than fetal components. In conclusion, IL-34 expression in embryonal components may induce macrophage chemotaxis in a paracrine manner, and tumor cell proliferation and chemoresistance in an autocrine manner. IL-34 is a potential therapeutic target for hepatoblastoma.
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