Targeting Immune Checkpoints to Eliminate Leukemia Stem Cells
Immune checkpoints (IC) are regulators of the immune system. Either they activate (stimulatory checkpoint molecules) or they inhibit (inhibitory checkpoint molecules) an immune cell. The generation of immune checkpoint inhibitors (ICI) that block the inhibitory checkpoint receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has revolutionized the treatment of different solid tumors. In contrast, ICI seem less efficacious in the treatment of leukemia. Chronic and acute myeloid leukemia (CML and AML) originate from a malignant leukemia stem cell (LSC) that resides at the top of a hierarchical differentiation tree and gives rise to more differentiated malignant cells. LSCs are resistant to conventional chemotherapy, radiotherapy and probably also tyrosine kinase inhibitors and are therefore the main cause of relapse after initial successful therapy. The interaction with surrounding bone marrow (BM) niche cells crucially contributes to the therapy resistance of LSCs. Immune cells, although an integral part of the BM microenvironment, are not considered as classical niche cells. However, CD4+, CD8+ and NK cells interact with LSCs via soluble mediators and via stimulatory and inhibitory immune checkpoints. In contrast to most solid tumors, LSCs not only express ligands that activate or inhibit a specific immune response but also express immune checkpoint receptors. We have shown that the expression of the co-stimulatory receptors CD27 and lymphotoxin beta receptor (LTbR) regulates self-renewal of CML LSCs and mediates resistance to therapy. We recently showed in preclinical experiments and in a clinical phase 1/2 trial that targeting the CD27 ligand CD70 eliminates LSCs in AML patients. However, a detailed understanding of immune checkpoints in the regulation of LSCs is lacking. In the current application, we will functionally address the role of defined ICs of the tumor necrosis factor receptor (TNFR) family (CD70/CD27 and LIGHT/LTbR) in the regulation of LSCs and will perform an in-vivo CRISPR-Cas9 knock out (KO)-screen to assess the relative contribution of additional ICs. Together, these experiments will help to investigate the possibility of manipulating ICs in order to target LSCs.
(funded by the Swiss National Science Foundation).
