[HTML][HTML] Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma

V Huber, V Vallacchi, V Fleming, X Hu… - The Journal of …, 2018 - Am Soc Clin Investig
V Huber, V Vallacchi, V Fleming, X Hu, A Cova, M Dugo, E Shahaj, R Sulsenti, E Vergani…
The Journal of clinical investigation, 2018Am Soc Clin Investig
The accrual of myeloid-derived suppressor cells (MDSCs) represents a major obstacle to
effective immunotherapy in cancer patients, but the mechanisms underlying this process in
the human setting remain elusive. Here, we describe a set of microRNAs (miR-146a, miR-
155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, miR-99b) that are associated with
MDSCs and resistance to treatment with immune checkpoint inhibitors in melanoma
patients. The miRs were identified by transcriptional analyses as being responsible for the …
The accrual of myeloid-derived suppressor cells (MDSCs) represents a major obstacle to effective immunotherapy in cancer patients, but the mechanisms underlying this process in the human setting remain elusive. Here, we describe a set of microRNAs (miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, miR-99b) that are associated with MDSCs and resistance to treatment with immune checkpoint inhibitors in melanoma patients. The miRs were identified by transcriptional analyses as being responsible for the conversion of monocytes into MDSCs (CD14+HLA-DRneg cells) mediated by melanoma extracellular vesicles (EVs) and were shown to recreate MDSC features upon transfection. In melanoma patients, these miRs were increased in circulating CD14+ monocytes, plasma, and tumor samples, where they correlated with the myeloid cell infiltrate. In plasma, their baseline levels clustered with the clinical efficacy of CTLA-4 or programmed cell death protein 1 (PD-1) blockade. Hence, MDSC-related miRs represent an indicator of MDSC activity in cancer patients and a potential blood marker of a poor immunotherapy outcome.
The Journal of Clinical Investigation