Targeting Cytokine Therapy to the Pancreatic Tumor Microenvironment Using PD-L1–Specific VHHs
| Autor: | Quang-Dé Nguyen, Ulrich H. von Andrian, Novalia Pishesha, Michael Dougan, Olga S. Blomberg, Munir Mosaheb, Paul M Tyler, Hidde L. Ploegh, Patrick T. Bruck, Mariah M. Servos, Jessica R. Ingram, Hee-Jin Jeong, Mohammad Rashidian, Lestat R. Ali, Stephanie K. Dougan |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Cell Survival medicine.medical_treatment Immunology Melanoma Experimental B7-H1 Antigen Article Mice 03 medical and health sciences 0302 clinical medicine Pancreatic tumor Cell Line Tumor Pancreatic cancer PD-L1 Tumor Microenvironment Animals Humans Medicine Molecular Targeted Therapy Tumor microenvironment biology Cytokine Therapy business.industry Melanoma Single-Domain Antibodies medicine.disease Pancreatic Neoplasms Disease Models Animal 030104 developmental biology Cytokine 030220 oncology & carcinogenesis biology.protein Cancer research Cytokines business CD8 |
| Zdroj: | Cancer Immunology Research. 6:389-401 |
| ISSN: | 2326-6074 2326-6066 |
| Popis: | Cytokine-based therapies for cancer have not achieved widespread clinical success because of inherent toxicities. Treatment for pancreatic cancer is limited by the dense stroma that surrounds tumors and by an immunosuppressive tumor microenvironment. To overcome these barriers, we developed constructs of single-domain antibodies (VHHs) against PD-L1 fused with IL-2 and IFNγ. Targeting cytokine delivery in this manner reduced pancreatic tumor burden by 50%, whereas cytokines fused to an irrelevant VHH, or blockade of PD-L1 alone, showed little effect. Targeted delivery of IL-2 increased the number of intratumoral CD8+ T cells, whereas IFNγ reduced the number of CD11b+ cells and skewed intratumoral macrophages toward the display of M1-like characteristics. Imaging of fluorescent VHH–IFNγ constructs, as well as transcriptional profiling, demonstrated targeting of IFNγ to the tumor microenvironment. Many tumors and tumor-infiltrating myeloid cells express PD-L1, rendering them potentially susceptible to this form of targeted immunotherapy. Cancer Immunol Res; 6(4); 389–401. ©2018 AACR. |
| Databáze: | OpenAIRE |
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