Targeting Arg-1 and PD-L1 in M2-Tumor Associated Macrophages Impairs Juvenile Myelomonocytic Leukemia (JMML) Cell Proliferation and Migration

Background and Hypothesis: Tumor-associated macrophages (TAMs) are a key component of tumor-infiltrating immune cells. They largely characterized into M1 or M2 types. TAMs express an anti-inflammatory M2-like phenotype, promote tumor progression. However, the role M2-TAMs in driving disease pathogenesis patients with Juvenile myelomonocytic leukemia (JMML), rare form pediatric driven to large extent by mutations PTPN11 gene, which encodes phosphatase SHP2 is unclear. We hypothesized that JMML, inflammatory myeloid cells including neutrophils higher levels arginase-1 (Arg-1) PD-L1, may contribute local suppression responses support development JMML.
 Methods: To study how alterations M1/M2 JMML development, we utilized mouse model bearing Shp2E76K mutation (Ptpn11E76K/+) manifests cardinal features human JMML. Shp2E76K/+ enhance function bone marrow derived (BMDMs), T-cell suppression.
 Results: Our analysis bulk RNA-sequence data from 90 showed increase expression Arg-1 PD-1. Furthermore, single cell RNA-seq 4 revealed M2-macrophage markers/genes. results show M2-TAMs, PD-L1 elevated BM spleens mice compared WT. Moreover, were also BMDMs The have greater proliferation migration potential WT BMDMs, was significantly reduced inhibiting PD-L1.
 Conclusion: arginase-1, create pro-tumor microenvironment, likely contributes growth Inhibition novel therapeutic approach treat