Ardolino, M. | Search bioRxiv

bioRxiv2021

A small molecule drug screening identifies colistin sulfate as an enhancer of Natural Killer cell cytotoxicity.

Because of their crucial role in tumor immunity, NK cells have quickly become a prime target for immunotherapies, with adoptive transfer of NK cells and the use of NK cell engagers quickly moving to clinical stage. On the other hand, only few studies have focused on small molecule drugs capable of unleashing NK cell against cancer. In this context, repurposing small molecule is an attractive strategy to identify new immunotherapies from already approved drugs. Here, we screened 1,200 FDA-approved drugs from the Prestwick Chemical Library, to identify compounds that increase NK cell cytotoxic potential. Using a high-throughput luciferase-release cytotoxicity assay, we found that the antibiotic colistin sulfate increased cytotoxicity of human NK cells towards cancer cells. The effect of colistin was short lived and was not observed when NK cells were pretreated with the drug, showing how NK cell activity was potentiated only when the compound was present at the time of recognition of cancer cells. Further studies are needed to uncover the mechanism of action and the pre-clinical efficacy of colistin sulfate in mouse cancer models.

immunology↗

bioRxiv2020

NK cells acquire PD-1 from the membrane of tumor cells.

Leucocytes often perform trogocytosis, the process by which cells acquire parts of the plasma membrane from interacting cells. Accumulating evidence indicates that trogocytosis modulates immune responses, but the underlying molecular mechanisms are unclear. Here, using two mouse models of leukemia, we found that cytotoxic lymphocytes perform trogocytosis at high rates with tumor cells. While performing trogocytosis, both Natural Killer and CD8+ T cells acquire the checkpoint receptor PD-1 from leukemia cells. In vitro and in vivo investigation revealed that PD-1 protein found on the surface of Natural Killer cells, rather than being endogenously expressed, was derived entirely from leukemia cells. Mechanistically, SLAM receptors were essential for PD-1 trogocytosis. PD-1 acquired via trogocytosis actively suppressed anti-tumor immunity, as revealed by the positive outcome of PD-1 blockade in PD-1-deficient mice. PD-1 trogocytosis was corroborated in patients with clonal plasma cell disorders, where Natural Killer cells that stained for PD-1 also stained for tumor cell markers. Our results, in addition to shedding light on a previously unappreciated mechanism underlying the presence of PD-1 on Natural Killer and cytotoxic T cells, reveal the immune-regulatory effect of membrane transfer occurring when immune cells contact tumor cells. Once sentence summaryNatural Killer cells are inhibited by PD-1 acquired from the surface of tumor cells via trogocytosis.

immunology↗