Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 4205-4220 |
| Number of pages | 16 |
| Journal | Clinical Cancer Research : an official journal of the American Association for Cancer Research |
| Volume | 27 |
| Issue number | 15 |
| DOIs | |
| Publication status | Published - 1 Aug 2021 |
Bibliographical note
AcknowledgmentsWe thank Mari Parsama, Teija Kanasuo, Sari M€aki, and Riikka Sj€oroos for excellent technical assistance, and the Cell Imaging and Cytometry Core Facilities
at Turku Bioscience Center for their help in mass cytometry and imaging. Mass spectrometry analysis was performed at the Turku Proteomics Facility, University of
Turku and Åbo Akademi University. The facility is supported by Biocenter Finland. The study was supported by Finnish Functional Genomics Centre, University of
Turku, Åbo Akademi, and Biocenter Finland. We also want to thank all the patients for participating in the clinical trial. A humble recognition should be addressed to
Maria Lahtinen and Mari Kimpanp€a€a for managing patient sample logistics at Faron Pharmaceuticals Ltd., and Maria Jokinen, Maria Oliveira, and Jarna
Hannukainen at Faron Pharmaceuticals Ltd. and Laura Gardner at SimbecOrion for clinical management of the MATINS study. This study was funded
by the Academy of Finland (A. Takeda, T. L€onnberg, S. Jalkanen, and M. Hollmen), Emil Aaltonen Foundation (R. Virtakoivu), Maud Kuistila Memorial Foundation, Oskar O€flund Foundation, Ida Montin Foundation (all to M. Viitala), Cancer Research UK fellowship C53575/A29959 (S. Shetty), Sigrid Juselius Foundation (M. Hollmen), and the Finnish Cancer Foundations (M. Viitala and M. Hollmen). This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant
agreement no. 960914. Faron Pharmaceuticals sponsored the MATINS trial.
©2021 The Authors; Published by the American Association for Cancer Research.
