PDZ Proteins SCRIB and DLG1 Regulate Myeloma Cell Surface CD86 Expression, Growth, and Survival

Abstract

Despite advances in the treatment of multiple myeloma (MM) in the past decades, the disease remains incurable, and understanding signals and molecules that can control myeloma growth and survival are important for the development of novel therapeutic strategies. One such molecule, CD86, regulates MM cell survival via its interaction with CD28 and signaling through its cytoplasmic tail. Although the CD86 cytoplasmic tail has been shown to be involved in drug resistance and can induce molecular changes in MM cells, its function has been largely unexplored. Here, we show that CD86 cytoplasmic tail has a role in trafficking CD86 to the cell surface. This is due in part to a PDZ-binding motif at its C-terminus which is important for proper trafficking from the Golgi apparatus. BioID analysis revealed 10 PDZ-domain containing proteins proximal to CD86 cytoplasmic tail in myeloma cells. Among them, we found the planar cell polarity proteins, SCRIB and DLG1, are important for proper CD86 surface expression and the growth and survival of myeloma cells. These findings indicate a mechanism by which myeloma cells confer cellular survival and drug resistance and indicate a possible motif to target for therapeutic gain. Implications: These findings demonstrate the importance of proper trafficking of CD86 to the cell surface in myeloma cell survival and may provide a new therapeutic target in this disease.

Myxoma Virus Combination Therapy Enhances Lenalidomide and Bortezomib Treatments for Multiple Myeloma

“…In the study of Gavile et al [73], it was revealed that CD86 is necessary for myeloma cell survival and drug resistance. Moreover, the cytoplasmic region of CD86 is important for triggering molecular changes, such as the upregulation of Interferon regulatory factor 4 and Integrin beta-1 in myeloma cells [74]. In our study, with the blockade of CD28, the entry of MYXV into myeloma cells was decreased in two of the four patients and increased in one.…”

Efficiency of Interferon-γ in Activating Dendritic Cells and Its Potential Synergy with Toll-like Receptor Agonists

“…This could occasionally be due to background noise, overlapping of cells, or aggregation of the PE fluorescent dye. Another possible explanation is the incomplete transport or trafficking of newly synthesized CD86 proteins from the Golgi apparatus to the cell membrane [ 46 ]. Nonetheless, these images suggested that CD86 was expressed by the dendritic cells or that the cells were activated by the treatment of IFN-γ and poly I:C simultaneously.…”

Integrating p53-associated genes and infiltrating immune cell characterization as a prognostic biomarker in multiple myeloma

“…Nonetheless, it is imperative to acknowledge that the immune response predictions inferred from TIDE were not substantially elevated, intimating a potential resistance of MM to anti-PD1 and anti-CTLA4 therapies. Further research is necessary to elucidate the intricate relationship profoundly and investigate the effectiveness of alternative immunotherapeutic strategies, such as targeting CD47 and CD86 [ [41] , [42] , [43] ]. To conclude, the development of the p53-TIC classifier enhances prognostic stratification in MM patients and facilitates personalized treatment plans, optimizing efficacy and minimizing side effects.…”