Deep Immune Profiling of Multiple Myeloma at Diagnosis and under Lenalidomide Maintenance Therapy.

The bone marrow microenvironment interacts with malignant cells and regulates cancer survival and immune evasion in multiple myeloma (MM). We investigated the immune profiles of longitudinal bone marrow samples from patients with newly diagnosed MM (n = 18) using cytometry by time-of-flight. The results before and during treatment were compared between patients with good (GR, n = 11) and bad (BR, n = 7) responses to lenalidomide/bortezomib/dexamethasone-based treatment. Before treatment, the GR group had a lower tumor cell burden and a higher number of T cells with a phenotype shifted toward CD8+ T cells expressing markers attributed to cytotoxicity (CD45RA and CD57), a higher abundance of CD8+ terminal effector cells, and a lower abundance of CD8+ naïve T cells. On natural killer (NK) cells, increased expression of CD56 (NCAM), CD57, and CD16 was seen at baseline in the GR group, indicating their maturation and cytotoxic potential. During lenalidomide-based treatment, the GR patients showed an increase in effector memory CD4+ and CD8+ T-cell subsets. These findings support distinct immune patterns in different clinical contexts, suggesting that deep immune profiling could be used for treatment guidance and warrants further exploration.

PKCepsilon regulation of an alpha5 integrin-ZO-1 complex controls lamellae formation in migrating cancer cells.

Disruption of intercellular adhesions, increased abundance of alpha(5)beta(1) integrin, and activation of protein kinase Cepsilon (PKCepsilon) correlate with invasion and unfavorable prognosis in lung cancer. However, it remains elusive how these distinct factors contribute to the invasive behavior of cancer cells. Persistent cell motility requires the formation of stable lamellae at the leading edge of a migrating cell. Here, we report that the tight junction protein zonula occludens-1 (ZO-1) preferentially interacts with alpha(5)beta(1) integrin at the lamellae of migrating cells. Disruption of ZO-1 binding to an internal PDZ-binding motif in the alpha(5) cytoplasmic tail prevented the polarized localization of ZO-1 and alpha(5) at the leading edge. Furthermore, silencing of alpha(5) integrin inhibited migration and invasion of lung cancer cells, and silencing of ZO-1 resulted in increased Rac activity and reduced directional cell motility. The formation of the alpha(5)-ZO-1 complex was dependent on PKCepsilon: Phosphorylation of ZO-1 at serine-168 regulated the subcellular localization of ZO-1 and thus controlled its association with alpha(5) integrin. In conclusion, PKCepsilon activation drives the formation of a spatially restricted, promigratory alpha(5)-ZO-1 complex at the leading edge of lung cancer cells.