Identification of a novel immature dendritic cell subset with potential pro-leukemic effects in leukemia...

Both intrinsic and microenvironmental factors contribute to the genesis and progression of leukemia. Dendritic cells (DCs) are important members of the immunomicroenvironment. The immature DCs (imDCs) and regulatory DCs (DCregs) participate in the formation of an immunosuppressive microenvironment that play adverse role in tumor progression. However, the characteristics of DCs in leukemia microenvironment have not been well established. Here, we identified a novel CD11c⁺MHCII^lo DC population (T-DC) accumulated in the mouse splenic T-ALL microenvironment. T-DCs exhibited an immature phenotype as they were characterized by low expression of MHCII molecules and co-stimulatory molecules such as CD86, CD83 and CD40. Database analysis revealed that low level expression of DC maturation-associated genes correlated with poor prognosis in leukemia patients. Furthermore, T-DCs promoted T-ALL progression contributed by their attenuated phagocytosis and CD4⁺ T cell activation potential. Moreover, RNA sequencing analysis demonstrated that T-DCs expressed low level of genes related to maturation and antigen processing. T-DCs showed similar expression pattern with DCregs and expressed high levels of immunosuppressive genes. In addition, single cell RNA sequencing demonstrated the heterogeneity of T-DCs, showing that they are mainly compose of cDC1s, cDC2s and macrophage-like DCs. Therefore, our findings uncover the critical role of a novel imDC subset in promoting leukemia progression through the suppression of T-cell immunity. These results may have significant implications for the development of immunotherapeutic strategies aiming at reversing immune evasion in leukemia and improving patient outcomes.