Background: Immunotherapy has received an increasing amount of attention in the field of multiple myeloma treatment because it has low-level toxicity however, there are very few studies on immunotherapy drug resistance. This study aimed to initially explore the relevant factors and possible mechanisms of immunotherapy drugs Elotuzumab (Elo) and Lenalidomides’ resistance both in vivo and in vitro.
Methods: Cell models which are resistant to Elotuzumab and Lenalidomide were constructed; Different expression genes in UW, UR, UE, and URE cell lines were detected by using gene expression microarray; RT-qPCR validated CCL20 mRNA expression of four cell lines and patient samples; Bioinformatics Analysis of CCL20 expressions in NDMM and RRMM; ELISA detected the presence of CCL20 in the plasma of MM patients; Recovered CCL20 levels could increase the sensitivity of drug-resistant cell lines to immunomodulatory drugs; Constructed lenalidomide-resistant (UR) mouse subcutaneous xenograft model to explore whether or not CCL20 and lenalidomide treatment influenced the tumor volume’s growth.
Results: Cell models of drug resistance were successfully constructed and we found that the mRNA expression of CCL20 was down-regulated in resistant UR, UE, and URE cell lines; RT-qPCR confirmed these, and also identified the downregulation of CCL20 in RRMM patients compared with NDMM; bioinformatics analysis found that the mRNA expression of CCL20 was also down-regulated in RRMM patients; Furthermore, RRMM patients were found to have lower levels of CCL20 protein in their plasma when compared to NDMM. CCL20 could increase the sensitivity of UR,UE, and URE cell lines to immunomodulatory drugs in vitro and in vivo.
Conclusions: The expression of CCL20 was decreased in lenalidomide and elotuzumab resistant U266 cells and RRMM patients.CCL20 could possibly increase the sensitivity of lenalidomide in vitro and in vivo.