Siglec-15 promotes evasion of adaptive immunity in B-cell acute lymphoblastic leukemia

Abstract Siglec-15 (Sig15) has been implicated as an immune checkpoint expressed in solid tumor-infiltrating macrophages and is being targeted clinical trials with monoclonal antibodies to normalize the tumor microenvironment stimulate anti-tumor immunity. However, role of Sig15 hematological malignancies remains undefined. mRNA protein expression levels were determined from publicly available databases, cell lines, primary patient samples. Human B acute lymphoblastic leukemia (B-ALL) lines used identify signaling pathways involved regulation expression. Secreted/soluble cytokine measured plasma children healthy controls. Knockdown knockout Siglec15 a murine model B-ALL was evaluate effect leukemia-derived on response leukemia. We observed pathological overexpression variety malignancies, including This driven by NF-κB activation, which also increased surface localization Sig15. found circulate at elevated correlated immune-suppressive milieu. Genetic inhibition promoted clearance system marked reversal immune-privileged bone marrow niche, expanded early effector CD8+ T cells reduction immunosuppressive cytokines. Thus, novel, potent molecule active that may be therapeutically activate lymphocytes against cells.