التفاصيل البيبلوغرافية
| العنوان: |
Systemic blockade of clever-1 elicits lymphocyte activation alongside checkpoint molecule downregulation in patients with solid tumors:results from a phase I/II clinical trial |
| المؤلفون: |
Virtakoivu, R. (Reetta), Rannikko, J. H. (Jenna H.), Viitala, M. (Miro), Vaura, F. (Felix), Takeda, A. (Akira), Lönnberg, T. (Tapio), Koivunen, J. (Jussi), Jaakkola, P. (Panu), Pasanen, A. (Annika), Shetty, S. (Shishir), de Jonge, M. J. (Maja J. A.), Robbrecht, D. (Debbie), Ma, Y. T. (Yuk Ting), Skyttä, T. (Tanja), Minchom, A. (Anna), Jalkanen, S. (Sirpa), Karvonen, M. K. (Matti K.), Mandelin, J. (Jami), Bono, P. (Petri), Hollmén, M. (Maija) |
| بيانات النشر: |
American Association for Cancer Research |
| سنة النشر: |
2021 |
| المجموعة: |
Jultika - University of Oulu repository / Oulun yliopiston julkaisuarkisto |
| الوصف: |
Purpose:: Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell–targeting therapies. Thus, agents able to reprogram macrophages toward a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of the macrophage scavenger receptor Clever-1 has shown benefit in inducing CD8⁺ T-cell–mediated antitumor responses in mouse models of cancer, which supports the clinical development of Clever-1–targeting antibodies for cancer treatment. Patients and Methods:: In this study, we analyzed the mode of action of a humanized IgG4 anti–Clever-1 antibody, FP-1305 (bexmarilimab), both in vitro and in patients with heavily pretreated metastatic cancer (n = 30) participating in part 1 (dose-finding) of a phase I/II open-label trial (NCT03733990). We studied the Clever-1 interactome in primary human macrophages in antibody pull-down assays and utilized mass cytometry, RNA sequencing, and cytokine profiling to evaluate FP-1305–induced systemic immune activation in patients with cancer. Results: Our pull-down assays and functional studies indicated that FP-1305 impaired multiprotein vacuolar ATPase–mediated endosomal acidification and improved the ability of macrophages to activate CD8⁺ T-cells. In patients with cancer, FP-1305 administration led to suppression of nuclear lipid signaling pathways and a proinflammatory phenotypic switch in blood monocytes. These effects were accompanied by a significant increase and activation of peripheral T-cells with indications of antitumor responses in some patients. Conclusions: Our results reveal a nonredundant role played by the receptor Clever-1 in suppressing adaptive immune cells in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch, potentially leading to intratumoral proinflammatory responses in patients with metastatic cancer. |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
application/pdf |
| اللغة: |
English |
| الإتاحة: |
http://urn.fi/urn:nbn:fi-fe2022022420733Test |
| حقوق: |
info:eu-repo/semantics/openAccess ; © 2021 The Authors; Published by the American Association for Cancer Research This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs International 4.0 License. ; https://creativecommons.org/licenses/by-nc-nd/4.0Test/ |
| رقم الانضمام: |
edsbas.1B73AD9B |
| قاعدة البيانات: |
BASE |
