mDKN-01, a Novel Anti-DKK1 mAb, Enhances Innate Immune Responses in the Tumor Microenvironment
| Autor: | Heidi Heath, Michael Haas, Michael H. Kagey, Walter Newman, James B. Rottman, Franziska Schuerpf |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Pembrolizumab Mice 03 medical and health sciences 0302 clinical medicine Immune system Neoplasms Tumor Microenvironment medicine Animals Humans Molecular Biology Tumor microenvironment Innate immune system biology business.industry Melanoma Antibodies Monoclonal Cancer medicine.disease Metastatic breast cancer Immunity Innate 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Intercellular Signaling Peptides and Proteins Antibody business |
| Zdroj: | Molecular Cancer Research. 19:717-725 |
| ISSN: | 1557-3125 1541-7786 |
| Popis: | Dickkopf-1 (DKK1), a secreted modulator of Wnt signaling, is overexpressed in many cancers, is often associated with worse clinical outcomes, and has been shown to have immunosuppressive effects. DKN-01 is an IgG4 clinical stage antibody that potently and specifically neutralizes human and murine DKK1 and has recently completed a promising study in combination with pembrolizumab in patients with gastric/gastroesophageal junction cancer. The purpose of this study is to characterize a murine version of DKN-01 (mDKN-01) and to better understand its mechanism of action. We examined the efficacy of mDKN-01 in both melanoma and metastatic breast cancer models. Immune depletion experiments revealed a requirement for natural killer (NK) but not B and T cells for tumor growth inhibition. mDKN-01 treatment promotes the induction of the NK-activating cytokines IL15 and IL33 as well as an enhanced recruitment of CD45+ cells. Other treatment-related changes include a reduction of Gr-1+CD11b+ myeloid-derived suppressor cells (MDSC) in the tumor and spleen and the upregulation of PD-L1 on MDSCs. In addition, mDKN-01 has a marked effect at reducing pulmonary metastases in the mouse 4T1 breast cancer model. Finally, the mDKN-01/anti-PD-1 combination was more effective at inhibiting melanoma growth than mDKN-01 alone. Taken together, our data demonstrate that mDKN-01 has efficacy by blocking the immunosuppressive effects of DKK1 in the tumor microenvironment (TME) and provides insight into the clinical activity observed with DKN-01–based treatment. Implications: mDKN-01 reverses a DKK1-mediated innate immune suppression in the TME and has additive efficacy with a PD-1 inhibitor. |
| Databáze: | OpenAIRE |
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