Characterization and spatial distribution of infiltrating lymphocytes in medullary, and lymphocyte-predominant triple negative breast cancers.

Medullary carcinoma of the breast (MedBC) is a rare histological type that accounts for less than 5% of all invasive breast cancers. Here, we performed an exploratory study aimed to determine whether imaging mass cytometry (IMC) can be used to characterize the immune infiltration and the spatial distribution heterogeneity in the rare subtype of MedBC compared to atypical MedBC and TNBC-TILS+ tumors. In both MedBC and TNBC-TILs+, there was a notable enrichment of immune cells in the peripheral regions of the tumors, whereas in atypical MedBC, the immune cells exhibited a central enrichment pattern. This distribution of infiltrated cells reflects an active immune recruitment correlated to more favorable prognosis. In MedBC, spatial analysis shows that immune cells are localized at a greater distance from the tumor cells. IMC highlights the heterogeneity of immune microenvironment across three main subtypes of breast tumors and could help to define distinct immune patterns.

Membrane-bound delta-4 notch ligand reduces the proliferative activity of primitive human hematopoietic CD34+CD38low cells while maintaining their LTC-IC potential.

To examine the role of the Notch ligand Delta-4 on hematopoietic stem cells, human CD34+CD38low cord blood cells were cocultured on S17 cells transduced with transmembrane Delta-4 (mbD4/S17) or an empty vector (C/S17). By the end of a 3-week culture, mbD4/S17 induced a 25-fold reduction in nucleated cell production, as compared to C/S17, by maintaining a higher proportion of cells in G0/G1 phase. A specific retention of a high proportion of CD34+ cells throughout the culture was observed with mbD4/S17, contrary to C/S17. Although mbD4/S17 promoted expansion of cells with the phenotype of committed lymphoid precursors (CD34+CD7+CD45RA+), these cells still retained their myeloid differentiation potential. mbD4/S17 maintained a higher LTC-IC frequency in output CD34+ cells, compared to C/S17, as in the subsets of cells having completed the same number of divisions on mbD4/S17. A Delta4-Fc protein (extracellular part of human Delta4 fused to Fc human IgG1 portion), immobilized on plastic, also reduced cell production and retained the LTC-IC potential. Transplantation of cells grown on mbD4/S17 into NOD/SCID mice showed no significant enhancement of the long-term repopulating ability. Thus, Delta4 appears to inhibit hematopoietic stem cell proliferation, in association with the maintenance of short-term lymphoid and myeloid repopulation capacity.