Systemic blockade of Clever-1 in patients with solid tumours elicits lymphocyte activation alongside checkpoint molecule downregulation

Macrophages are critical in driving an immunosuppressive tumour microenvironment that counteracts the efficacy of T-cell targeting therapies1. Thus agents, which can re-programme macrophages towards a pro-inflammatory state hold promise as novel immunotherapies for solid cancers2. Here we report that therapeutic targeting of a macrophage scavenger receptor, Clever-13, in heavily pre-treated metastatic cancer patients was able to induce a significant increase and activation of peripheral T-cells including downregulation of several immune checkpoint molecules. Transcriptional and mass cytometry analyses revealed treatment induced inflammatory conversion of blood monocytes, which was partly driven by impaired Clever-1 mediated scavenging. Identification of relevant peripheral signatures indicative of anti-tumour activity showed induction of an effector CD8 T-cell population that resulted from clonal expansion of cytotoxic CD8 T-cells. In some patients this was accompanied by features of increased accumulation of CD8 T-cells in post-treatment tumour biopsies. Our results reveal a non-redundant role played by the receptor Clever-1 in suppressing adaptive immune cell activation in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch leading to peripheral activation and potentially intra tumoural proinflammatory responses in metastatic cancer patients. Anti-Clever-1 treatment may therefore provide an attractive immunotherapeutic strategy in cancer. Droplet-based single-cell RNA sequencing (scRNA-seq) with TCR sequencing of peripheral blood T and B cells from cycles 1 and 4 of the responder patient. scRNA-seq and TCRab-libraries was prepared using 10X Genomics Chromium Next GEM Single Cell 5' Library & Gel Bead Kit according to manufacture's instructions. Libraries were sequenced on NovaSeq.