Abstract

Abstract The immune checkpoint CLEC-1 (C-type lectin domain family 1 member A) expressed by dendritic cells, macrophages, and endothelial cells, has been shown as a necrotic receptor playing a critical role in immune response modulation during sterile inflammation. Several studies have highlighted CLEC-1's potential as a target for immunotherapeutic strategies. Absence of CLEC-1 signaling by genetic ablation or antibody blockade has been shown to promote anti-tumor response by increasing the cross-presentation of dead cell-associated antigens by type 1 conventional dendritic cells and by enhancing T-cell activation. Furthermore, this CLEC-1 signaling blockade has also recently been shown to increase an acute inflammatory response in a model of liver tissue damage induced by the acetaminophen (APAP) intoxication by exacerbating the recruitment of neutrophils at the site of inflammation. Using LC/mS, we discovered different CLEC-1 ligands, such as TRIM21, HRG and other intracellular or plasma membrane molecules. Although their biological activities following interaction with CLEC-1 remain to be fully investigated, we observed that a cell stress induced by radiation or by different chemotherapeutic class agents such as cyclophosphamide (CPA), oxaliplatin, vorinostat and others, increase the expression of CLEC-1 ligand(s) on necrotic and live cells. Consequently, we found in vivo that CPA treatment combined with the absence of Clec1a gene more strongly induced tumor volume reduction than in the presence of Clec1a in fibrosarcoma (MCA) and colorectal (MC38) mouse models. We developed and selected two anti-CLEC-1 antagonist antibodies harboring different properties (e.g. affinity, epitope). Using humanized CLEC-1 mice, we showed, in a orthotopic mouse model of hepatocarcinoma (Hepa1.6) exhibiting resistance to anti-PD1/PDL1 mAb therapy, that these anti-CLEC-1 antibodies in monotherapy significantly increase overall mice survival compared to corresponding isotype control treatment (3 independent experiments, n=32 for each treatment, p<0.002). Moreover, we confirmed also the therapeutic effect of these anti-CLEC-1 antibodies in combination with CPA in the ectopic MC38 model (n=18, 2 independent experiments). Altogether, our results further dissect the mechanism of action of the myeloid checkpoint CLEC-1 in its ability to impair anti-tumor immunity and support its target with antagonist antibody for cancer immunotherapy. Citation Format: Etienne Foucher, Mylène Deramé, Justine Durand, Marion Drouin, Camille Ligeron, Caroline Mary, Vanessa Gauttier, Isabelle Girault, Emmanuelle Wilhelm, Virginie Thepenier, Cécile Batty, Géraldine Teppaz, Ariane Desselle, Marine Malloci, Irène Baccelli, Marion Colonello, Stéphanie Neyton, Elise Chiffoleau, Aurore Morello, Nicolas Poirier. First in class Anti-CLEC-1A myeloid checkpoint antibodies for the treatment of solid tumors with monotherapy and combination therapy efficacies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7293.