TY - JOUR
T1 - Systemic blockade of Clever-1 elicits lymphocyte activation alongside checkpoint molecule downregulation in patients with solid tumors
T2 - results from a phase I/II clinical trial
AU - Virtakoivu, Reetta
AU - Rannikko, Jenna H.
AU - Viitala, Miro
AU - Vaura, Felix
AU - Takeda, Akira
AU - Lönnberg, Tapio
AU - Koivunen, Jussi
AU - Jaakkola, Panu
AU - Pasanen, Annika
AU - Shetty, Shishir
AU - Jonge, Maja J. A. de
AU - Robbrecht, Debbie
AU - Ma, Yuk Ting
AU - Skyttä, Tanja
AU - Minchom, Anna
AU - Jalkanen, Sirpa
AU - Karvonen, Matti K.
AU - Mandelin, Jami
AU - Bono, Petri
AU - Hollmen, Maija
PY - 2021/6/2
Y1 - 2021/6/2
N2 - Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell-targeting therapies. Thus, agents able to reprogram macrophages towards a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of a 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. In this study, we analyzed the mode of action of a humanized IgG4 anti-Clever-1 antibody, FP-1305 ( ), both and in heavily pretreated metastatic cancer patients ( =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 cancer patients. 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 cancer patients, 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. Our results reveal a non-redundant 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 metastatic cancer patients.
AB - Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell-targeting therapies. Thus, agents able to reprogram macrophages towards a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of a 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. In this study, we analyzed the mode of action of a humanized IgG4 anti-Clever-1 antibody, FP-1305 ( ), both and in heavily pretreated metastatic cancer patients ( =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 cancer patients. 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 cancer patients, 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. Our results reveal a non-redundant 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 metastatic cancer patients.
UR - http://www.scopus.com/inward/record.url?scp=85111686418&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-4862
DO - 10.1158/1078-0432.CCR-20-4862
M3 - Article
SN - 1078-0432
VL - 27
SP - 4205
EP - 4220
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 15
ER -